rs199572804

Variant names:

• chr11-17509638-C-T
• rs199572804
• NM_153676.4:c.1731G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-17509638-C-T
• chr11-17509638-C-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_153676.4(USH1C):​c.1731G>A​(p.Pro577Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,214,584 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 0.00010 (0 hom., cov: 18)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: USH1C NM_153676.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.68
• Publications: 2 publications found

Genes affected

USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

USH1C Gene-Disease associations (from GenCC):

• Usher syndrome type 1C

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

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-17509638-C-T is Benign according to our data. Variant chr11-17509638-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 47978.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-5.68 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153676.4. 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
	USH1C	NM_153676.4	MANE Select	c.1731G>A	p.Pro577Pro	synonymous	Exon 18 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.1285-7658G>A		intron	N/A	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.1470+2264G>A		intron	N/A	NP_001427608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.1731G>A	p.Pro577Pro	synonymous	Exon 18 of 27	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1285-7658G>A		intron	N/A	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.1228-7658G>A		intron	N/A	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.000101 AC: 7 AN: 69378 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.000179

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: 0.000110

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000161 AC: 3 AN: 186652 AF XY: 0.0000293

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000824

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000393 AC: 45 AN: 1145206 Hom.: 0 Cov.: 40 AF XY: 0.0000551 AC XY: 31 AN XY: 562470

African (AFR) AF: 0.0000381 AC: 1 AN: 26250

American (AMR) AF: 0.00 AC: 0 AN: 29694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16240

East Asian (EAS) AF: 0.0000985 AC: 2 AN: 20298

South Asian (SAS) AF: 0.0000174 AC: 1 AN: 57566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4232

European-Non Finnish (NFE) AF: 0.0000410 AC: 38 AN: 927762

Other (OTH) AF: 0.0000708 AC: 3 AN: 42394

GnomAD4 genome AF: 0.000101 AC: 7 AN: 69378 Hom.: 0 Cov.: 18 AF XY: 0.0000611 AC XY: 2 AN XY: 32744

African (AFR) AF: 0.000179 AC: 3 AN: 16760

American (AMR) AF: 0.00 AC: 0 AN: 4852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1898

East Asian (EAS) AF: 0.00 AC: 0 AN: 3008

South Asian (SAS) AF: 0.00 AC: 0 AN: 1976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 140

European-Non Finnish (NFE) AF: 0.000110 AC: 4 AN: 36426

Other (OTH) AF: 0.00 AC: 0 AN: 850

Alfa AF: 0.0000251 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.23
DANN	Benign	0.52
PhyloP100		-5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199572804; hg19: chr11-17531185; COSMIC: COSV50013948; COSMIC: COSV50013948;