NM_173477.5:c.1012G>T

Variant names:

• chr17-74919824-C-A
• rs151242039
• NM_173477.5:c.1012G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173477.5(USH1G):​c.1012G>T​(p.Gly338Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G338R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH1G NM_173477.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.45
• Publications: 0 publications found

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]

USH1G Gene-Disease associations (from GenCC):

• Usher syndrome type 1G

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39429235).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173477.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1G	NM_173477.5	MANE Select	c.1012G>T	p.Gly338Trp	missense	Exon 2 of 3	NP_775748.2
	USH1G	NM_001282489.3		c.703G>T	p.Gly235Trp	missense	Exon 2 of 3	NP_001269418.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1G	ENST00000614341.5	TSL:1 MANE Select	c.1012G>T	p.Gly338Trp	missense	Exon 2 of 3	ENSP00000480279.1	Q495M9
	USH1G	ENST00000579243.1	TSL:2	n.*611G>T		non_coding_transcript_exon	Exon 2 of 3	ENSP00000462568.1	J3KSN5
	USH1G	ENST00000579243.1	TSL:2	n.*611G>T		3_prime_UTR	Exon 2 of 3	ENSP00000462568.1	J3KSN5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.0056	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.5
PrimateAI	Uncertain	0.55	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.89	P
Vest4		0.52
MutPred		0.37		Loss of methylation at R343 (P = 0.0442)
MVP		0.29
ClinPred		0.73	D
GERP RS		3.3
Varity_R		0.15
gMVP		0.36

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

Other links and lift over

dbSNP: rs151242039; hg19: chr17-72915919;