NM_153676.4:c.2611G>A

Variant names:

• chr11-17495613-C-T
• rs56165709
• NM_153676.4:c.2611G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_153676.4(USH1C):​c.2611G>A​(p.Ala871Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00529 in 1,614,210 control chromosomes in the GnomAD database, including 21 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (21 hom.)
• Consequence: USH1C NM_153676.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.161
• Publications: 10 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007481545).
• BP6: Variant 11-17495613-C-T is Benign according to our data. Variant chr11-17495613-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48009.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00329 (501/152338) while in subpopulation NFE AF = 0.00531 (361/68030). AF 95% confidence interval is 0.00486. There are 0 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR,Unknown gene

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.2611G>A	p.Ala871Thr	missense	Exon 26 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.1646+1145G>A		intron	N/A	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.1832+1145G>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.2611G>A	p.Ala871Thr	missense	Exon 26 of 27	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1646+1145G>A		intron	N/A	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.1589+1145G>A		intron	N/A	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00532

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00313 AC: 788 AN: 251482 AF XY: 0.00308

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00528

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00550 AC: 8038 AN: 1461872 Hom.: 21 Cov.: 31 AF XY: 0.00535 AC XY: 3892 AN XY: 727236

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00284 AC: 127 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00102 AC: 88 AN: 86256

European-Finnish (FIN) AF: 0.00170 AC: 91 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00669 AC: 7444 AN: 1112006

Other (OTH) AF: 0.00407 AC: 246 AN: 60392

GnomAD4 genome AF: 0.00329 AC: 501 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.00303 AC XY: 226 AN XY: 74502

African (AFR) AF: 0.000938 AC: 39 AN: 41578

American (AMR) AF: 0.00431 AC: 66 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00531 AC: 361 AN: 68030

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00466 Hom.: 5

Bravo AF: 0.00359

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00524 AC: 45

ExAC AF: 0.00292 AC: 355

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00468

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 18A (1)
-	-	1	USH1C-related disorder (1)
-	1	-	Usher syndrome type 1C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.16
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.010
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0080	D
Vest4		0.29
MVP		0.20
MPC		0.061
ClinPred		0.0037	T
GERP RS		1.5
gMVP		0.51
Mutation Taster		=97/3	polymorphism

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: rs56165709; hg19: chr11-17517160;