NM_173477.5:c.972T>C

Variant names:

• chr17-74919864-A-G
• rs773660538
• NM_173477.5:c.972T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_173477.5(USH1G):​c.972T>C​(p.Ser324Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000479 in 1,605,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: USH1G NM_173477.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0850
• 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: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 17-74919864-A-G is Benign according to our data. Variant chr17-74919864-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 228199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.085 with no splicing effect.

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.972T>C	p.Ser324Ser	synonymous	Exon 2 of 3	NP_775748.2
	USH1G	NM_001282489.3		c.663T>C	p.Ser221Ser	synonymous	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.972T>C	p.Ser324Ser	synonymous	Exon 2 of 3	ENSP00000480279.1	Q495M9
	USH1G	ENST00000579243.1	TSL:2	n.*571T>C		non_coding_transcript_exon	Exon 2 of 3	ENSP00000462568.1	J3KSN5
	USH1G	ENST00000579243.1	TSL:2	n.*571T>C		3_prime_UTR	Exon 2 of 3	ENSP00000462568.1	J3KSN5

Frequencies

GnomAD3 genomes AF: 0.0000332 AC: 5 AN: 150598 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000739

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250536 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000495 AC: 72 AN: 1455320 Hom.: 0 Cov.: 42 AF XY: 0.0000442 AC XY: 32 AN XY: 724176

African (AFR) AF: 0.00 AC: 0 AN: 33346

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39340

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000622 AC: 69 AN: 1109584

Other (OTH) AF: 0.0000500 AC: 3 AN: 60032

GnomAD4 genome AF: 0.0000332 AC: 5 AN: 150598 Hom.: 0 Cov.: 32 AF XY: 0.0000544 AC XY: 4 AN XY: 73532

African (AFR) AF: 0.00 AC: 0 AN: 41104

American (AMR) AF: 0.00 AC: 0 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 4980

South Asian (SAS) AF: 0.00 AC: 0 AN: 4606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000739 AC: 5 AN: 67642

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000340

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.66
PhyloP100		-0.085

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: rs773660538; hg19: chr17-72915959;