rs876657597

Positions:

• chr22-37772650-G-A
• chr22-37772650-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001039141.3(TRIOBP):​c.6986G>A​(p.Ser2329Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.02

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038983405).
• BP6: Variant 22-37772650-G-A is Benign according to our data. Variant chr22-37772650-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 228043.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.6986G>A	p.Ser2329Asn	missense_variant	23/24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5	c.1847G>A	p.Ser616Asn	missense_variant	13/14		NP_008963.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6986G>A	p.Ser2329Asn	missense_variant	23/24		NM_001039141.3	ENSP00000496394.1
TRIOBP	ENST00000403663.6	c.1847G>A	p.Ser616Asn	missense_variant	13/14	1		ENSP00000386026.2
TRIOBP	ENST00000344404.10	n.*6469G>A		non_coding_transcript_exon_variant	21/22	2		ENSP00000340312.6
TRIOBP	ENST00000344404.10	n.*6469G>A		3_prime_UTR_variant	21/22	2		ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249470 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135380

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461850 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 24, 2015

p.Ser2329Asn in exon 23 of TRIOBP: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, more than 40 mammals have a asparagine (Asn) at this position despite hi gh nearby amino acid conservation. In addition, computational prediction tools s uggest a low likelihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.015	T;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.61	.;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.039	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.80	N;N;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.97	N;.;N
REVEL	Benign	0.034
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;.;T
Polyphen		0.0010	B;B;.
Vest4		0.15
MutPred		0.18		Loss of phosphorylation at S2329 (P = 0.0469);Loss of phosphorylation at S2329 (P = 0.0469);.;
MVP		0.20
MPC		0.11
ClinPred		0.072	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.049

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657597; hg19: chr22-38168657;