rs191901426

Positions:

• chr22-37768157-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001039141.3(TRIOBP):​c.6556G>A​(p.Gly2186Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000423 in 1,612,906 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.49

Genes affected

TRIOBP (HGNC:17009): (TRIO and F-actin binding protein) This gene encodes a protein with an N-terminal pleckstrin homology domain and a C-terminal coiled-coil region. The protein interacts with trio, which is involved with neural tissue development and controlling actin cytoskeleton organization, cell motility and cell growth. The protein also associates with F-actin and stabilizes F-actin structures. Mutations in this gene have been associated with a form of autosomal recessive nonsyndromic deafness. Multiple alternatively spliced transcript variants that would encode different isoforms have been found for this gene, however some transcripts may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008279085).
• BP6: Variant 22-37768157-G-A is Benign according to our data. Variant chr22-37768157-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228040.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}. Variant chr22-37768157-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000429 (627/1460630) while in subpopulation MID AF= 0.00607 (35/5766). AF 95% confidence interval is 0.00449. There are 1 homozygotes in gnomad4_exome. There are 334 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.6556G>A	p.Gly2186Ser	missense_variant	19/24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5	c.1417G>A	p.Gly473Ser	missense_variant	9/14		NP_008963.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6556G>A	p.Gly2186Ser	missense_variant	19/24		NM_001039141.3	ENSP00000496394	A2
TRIOBP	ENST00000403663.6	c.1417G>A	p.Gly473Ser	missense_variant	9/14	1		ENSP00000386026	P2
TRIOBP	ENST00000344404.10	c.*6039G>A		3_prime_UTR_variant, NMD_transcript_variant	17/22	2		ENSP00000340312

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000438 AC: 108 AN: 246352 Hom.: 1 AF XY: 0.000471 AC XY: 63 AN XY: 133728

Gnomad AFR exome AF: 0.000330

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000729

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000609

Gnomad OTH exome AF: 0.000834

GnomAD4 exome AF: 0.000429 AC: 627 AN: 1460630 Hom.: 1 Cov.: 33 AF XY: 0.000460 AC XY: 334 AN XY: 726472

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000381

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74448

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000610 Hom.: 0

Bravo AF: 0.000397

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000498 AC: 2

ESP6500EA AF: 0.000599 AC: 5

ExAC AF: 0.000480 AC: 58

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TRIOBP p.Gly2186Ser variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs191901426), ClinVar (classified as likely benign‚Äã by Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine and GeneDx) and LOVD 3.0 (classified as likely benign). The variant was also identified in control databases in 114 of 277736 chromosomes (1 homozygous) at a frequency of 0.00041 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 6 of 7084 chromosomes (freq: 0.000847), South Asian in 22 of 30178 chromosomes (freq: 0.000729), European (non-Finnish) in 70 of 127052 chromosomes (freq: 0.000551), African in 8 of 23882 chromosomes (freq: 0.000335), Latino in 7 of 35074 chromosomes (freq: 0.0002) and Ashkenazi Jewish in 1 of 10298 chromosomes (freq: 0.000097), while the variant was not observed in the East Asian and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Gly2186 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	TRIOBP: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2015	p.Gly2186Ser in exon 19 of TRIOBP: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, 6 mammals (mouse, rat, tenrec, opossum, Tasmanian devil, and wallaby) ha ve a serine (Ser) at this position despite high nearby amino acid conservation. This variant has been identified in 0.1% (11/13630) of South Asian chromosomes a nd 0.06% (35/54590) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs191901426). -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2022	Variant summary: TRIOBP c.6556G>A (p.Gly2186Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 246352 control chromosomes in the gnomAD database, including 1 homozygote. c.6556G>A has been reported in the literature in an individual affected with Nonsyndromic Hearing Loss (Shearer_2013). This report does not provide unequivocal conclusions about association of the variant with Autosomal Recessive Nonsyndromic Hearing Loss 28. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.012	T;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.76	.;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.0083	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.14	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.84	N;.;N
REVEL	Benign	0.014
Sift	Benign	0.32	T;.;T
Sift4G	Benign	0.42	T;.;T
Polyphen		0.024	B;B;.
Vest4		0.16
MVP		0.25
MPC		0.26
ClinPred		0.011	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.064

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs191901426; hg19: chr22-38164164;