NM_005709.4:c.1243G>A

Variant names:

• chr11-17517442-C-T
• rs116996553
• NM_005709.4:c.1243G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005709.4(USH1C):​c.1243G>A​(p.Ala415Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 1,595,680 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A415V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0054 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (110 hom.)
• Consequence: USH1C NM_005709.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0690
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024359822).
• BP6: Variant 11-17517442-C-T is Benign according to our data. Variant chr11-17517442-C-T is described in ClinVar as Benign. ClinVar VariationId is 45425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005709.4. 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_005709.4	MANE Plus Clinical	c.1243G>A	p.Ala415Thr	missense	Exon 15 of 21	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_153676.4	MANE Select	c.1211-1152G>A		intron	N/A	NP_710142.1	Q9Y6N9-5
	USH1C	NM_001440679.1		c.1276G>A	p.Ala426Thr	missense	Exon 15 of 22	NP_001427608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1243G>A	p.Ala415Thr	missense	Exon 15 of 21	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.1186G>A	p.Ala396Thr	missense	Exon 14 of 20	ENSP00000436934.1	Q9Y6N9-4
	USH1C	ENST00000527720.5	TSL:1	c.1150G>A	p.Ala384Thr	missense	Exon 14 of 20	ENSP00000432944.1	Q9Y6N9-2

Frequencies

GnomAD3 genomes AF: 0.00537 AC: 817 AN: 152154 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.0593

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00849 AC: 1878 AN: 221180 AF XY: 0.00743

Gnomad AFR exome AF: 0.000804

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.000211

Gnomad EAS exome AF: 0.0624

Gnomad FIN exome AF: 0.00981

Gnomad NFE exome AF: 0.000183

Gnomad OTH exome AF: 0.00517

GnomAD4 exome AF: 0.00306 AC: 4413 AN: 1443408 Hom.: 110 Cov.: 32 AF XY: 0.00293 AC XY: 2096 AN XY: 715952

African (AFR) AF: 0.000422 AC: 14 AN: 33186

American (AMR) AF: 0.0181 AC: 767 AN: 42408

Ashkenazi Jewish (ASJ) AF: 0.000194 AC: 5 AN: 25764

East Asian (EAS) AF: 0.0711 AC: 2778 AN: 39066

South Asian (SAS) AF: 0.000964 AC: 80 AN: 82992

European-Finnish (FIN) AF: 0.00871 AC: 453 AN: 52028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.0000617 AC: 68 AN: 1102488

Other (OTH) AF: 0.00415 AC: 248 AN: 59738

GnomAD4 genome AF: 0.00538 AC: 819 AN: 152272 Hom.: 18 Cov.: 32 AF XY: 0.00658 AC XY: 490 AN XY: 74464

African (AFR) AF: 0.00106 AC: 44 AN: 41566

American (AMR) AF: 0.0203 AC: 311 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.0600 AC: 310 AN: 5164

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00222 Hom.: 7

Bravo AF: 0.00599

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00644 AC: 781

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Usher syndrome type 1C (2)
-	-	1	USH1C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.3
DANN	Benign	0.59
DEOGEN2	Benign	0.065	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.069
PROVEAN	Benign	0.010	N
REVEL	Benign	0.0040
Sift	Benign	0.37	T
Sift4G	Benign	0.63	T
Polyphen		0.0040	B
Vest4		0.11
MVP		0.15
ClinPred		0.000038	T
GERP RS		1.6
Varity_R		0.025
Mutation Taster		=99/1	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: rs116996553; hg19: chr11-17538989; COSMIC: COSV50020417; COSMIC: COSV50020417;