rs61729060

Positions:

• chr22-37769332-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001039141.3(TRIOBP):​c.6806A>G​(p.Asn2269Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,611,514 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (9 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.58

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029654205).
• BP6: Variant 22-37769332-A-G is Benign according to our data. Variant chr22-37769332-A-G is described in ClinVar as [Benign]. Clinvar id is 227128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37769332-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00575 (876/152370) while in subpopulation AFR AF= 0.0197 (821/41594). AF 95% confidence interval is 0.0186. There are 6 homozygotes in gnomad4. There are 421 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.6806A>G	p.Asn2269Ser	missense_variant	21/24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5	c.1667A>G	p.Asn556Ser	missense_variant	11/14		NP_008963.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6806A>G	p.Asn2269Ser	missense_variant	21/24		NM_001039141.3	ENSP00000496394	A2
TRIOBP	ENST00000403663.6	c.1667A>G	p.Asn556Ser	missense_variant	11/14	1		ENSP00000386026	P2
TRIOBP	ENST00000344404.10	c.*6289A>G		3_prime_UTR_variant, NMD_transcript_variant	19/22	2		ENSP00000340312

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 872 AN: 152252 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00134 AC: 325 AN: 242666 Hom.: 1 AF XY: 0.00102 AC XY: 135 AN XY: 132620

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.00129

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000563

Gnomad SAS exome AF: 0.000298

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.000681

GnomAD4 exome AF: 0.000609 AC: 888 AN: 1459144 Hom.: 9 Cov.: 34 AF XY: 0.000539 AC XY: 391 AN XY: 725812

Gnomad4 AFR exome AF: 0.0182

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000981

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00575 AC: 876 AN: 152370 Hom.: 6 Cov.: 32 AF XY: 0.00565 AC XY: 421 AN XY: 74510

Gnomad4 AFR AF: 0.0197

Gnomad4 AMR AF: 0.00215

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00182 Hom.: 0

Bravo AF: 0.00639

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0164 AC: 65

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.00167 AC: 202

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Asn2269Ser in Exon 21 of TRIOBP: This variant is not expected to have clinical s ignificance because it has been identified in 1.6% (54/3292) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs61729060). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.3
DANN	Benign	0.86
DEOGEN2	Benign	0.037	T;T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.71	.;T;T
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.3	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.93	N;.;N
REVEL	Benign	0.046
Sift	Benign	0.18	T;.;T
Sift4G	Benign	0.50	T;.;T
Polyphen		0.0020	B;B;.
Vest4		0.14
MVP		0.24
MPC		0.091
ClinPred		0.0010	T
GERP RS		1.2
Varity_R		0.029
gMVP		0.12

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61729060; hg19: chr22-38165339;