rs151242039

chr17-74919824-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_173477.5(USH1G):c.1012G>A(p.Gly338Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000386 in 1,613,010 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: USH1G NM_173477.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.45

Genes affected

USH1G (HGNC:16356): (USH1 protein network component sans) This gene encodes a protein that contains three ankyrin domains, a class I PDZ-binding motif and a sterile alpha motif. The encoded protein interacts with harmonin, which is associated with Usher syndrome type 1C. This protein plays a role in the development and maintenance of the auditory and visual systems and functions in the cohesion of hair bundles formed by inner ear sensory cells. Mutations in this gene are associated with Usher syndrome type 1G (USH1G). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004409492).
• BP6: Variant 17-74919824-C-T is Benign according to our data. Variant chr17-74919824-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000663 (101/152342) while in subpopulation AMR AF= 0.00261 (40/15306). AF 95% confidence interval is 0.00197. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1G	NM_173477.5	c.1012G>A	p.Gly338Arg	missense_variant	2/3	ENST00000614341.5
USH1G	NM_001282489.3	c.703G>A	p.Gly235Arg	missense_variant	2/3
USH1G	XM_011524296.2	c.703G>A	p.Gly235Arg	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1G	ENST00000614341.5	c.1012G>A	p.Gly338Arg	missense_variant	2/3	1	NM_173477.5	P1
USH1G	ENST00000579243.1	c.*611G>A		3_prime_UTR_variant, NMD_transcript_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.000663 AC: 101 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.000749 AC: 187 AN: 249690 Hom.: 1 AF XY: 0.000687 AC XY: 93 AN XY: 135432

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00787

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000357 AC: 521 AN: 1460668 Hom.: 2 Cov.: 41 AF XY: 0.000355 AC XY: 258 AN XY: 726676

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.00785

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000644 AC XY: 48 AN XY: 74502

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.00103

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000552 AC: 67

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 13, 2017	The p.Gly338Arg variant in USH1G is not expected to have clinical significance b ecause it has been identified in 0.75% (76/10120) of Ashkenazi Jewish chromosome s including 1 homozygote by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs151242039). The glycine (Gly) at position 338 is not well conserved in mammals or evolutionary distant species, and at least 2 ma mmals (lesser Egyptian jerboa, elephant) carry an arginine (Arg), supporting tha t the change at this position is tolerated. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 13, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2020	This variant is associated with the following publications: (PMID: 17896313) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2023	- -

USH1G-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	16
Dann	Benign	0.96
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.56	T
Sift4G	Uncertain	0.043	D
Polyphen		0.0	B
Vest4		0.31
MutPred		0.35		Gain of sheet (P = 0.0166);
MVP		0.28
ClinPred		0.021	T
GERP RS		3.3
Varity_R		0.11
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs151242039; hg19: chr17-72915919;