NM_153676.4:c.1414-34G>A

Variant names:

• chr11-17510555-C-T
• rs2237964
• NM_153676.4:c.1414-34G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_153676.4(USH1C):​c.1414-34G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,487,244 control chromosomes in the GnomAD database, including 16,781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2492 hom., cov: 32)
  • Exomes 𝑓: 0.14 (14289 hom.)
• Consequence: USH1C NM_153676.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.821
• Publications: 7 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 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• autosomal recessive nonsyndromic hearing loss 18A

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 11-17510555-C-T is Benign according to our data. Variant chr11-17510555-C-T is described in ClinVar as Benign. ClinVar VariationId is 262731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	NM_153676.4	MANE Select	c.1414-34G>A		intron	N/A	NP_710142.1
	USH1C	NM_005709.4	MANE Plus Clinical	c.1284+6846G>A		intron	N/A	NP_005700.2
	USH1C	NM_001440679.1		c.1470+1347G>A		intron	N/A	NP_001427608.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.1414-34G>A		intron	N/A	ENSP00000005226.7
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.1284+6846G>A		intron	N/A	ENSP00000317018.4
	USH1C	ENST00000527020.5	TSL:1	c.1227+6846G>A		intron	N/A	ENSP00000436934.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25378 AN: 152012 Hom.: 2486 Cov.: 32

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0905

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.0986

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.168

GnomAD2 exomes AF: 0.162 AC: 40512 AN: 250136 AF XY: 0.161

Gnomad AFR exome AF: 0.271

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.0761

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.137 AC: 182540 AN: 1335114 Hom.: 14289 Cov.: 21 AF XY: 0.139 AC XY: 93664 AN XY: 671606

African (AFR) AF: 0.274 AC: 8503 AN: 31054

American (AMR) AF: 0.230 AC: 10237 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4249 AN: 25426

East Asian (EAS) AF: 0.0921 AC: 3595 AN: 39024

South Asian (SAS) AF: 0.266 AC: 22258 AN: 83814

European-Finnish (FIN) AF: 0.102 AC: 5391 AN: 52890

Middle Eastern (MID) AF: 0.223 AC: 1221 AN: 5480

European-Non Finnish (NFE) AF: 0.119 AC: 118558 AN: 996934

Other (OTH) AF: 0.152 AC: 8528 AN: 56016

GnomAD4 genome AF: 0.167 AC: 25407 AN: 152130 Hom.: 2492 Cov.: 32 AF XY: 0.167 AC XY: 12391 AN XY: 74370

African (AFR) AF: 0.264 AC: 10948 AN: 41468

American (AMR) AF: 0.180 AC: 2747 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 575 AN: 3470

East Asian (EAS) AF: 0.0905 AC: 468 AN: 5172

South Asian (SAS) AF: 0.265 AC: 1273 AN: 4810

European-Finnish (FIN) AF: 0.0986 AC: 1045 AN: 10596

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7910 AN: 68004

Other (OTH) AF: 0.169 AC: 356 AN: 2112

Alfa AF: 0.142 Hom.: 2666

Bravo AF: 0.176

Asia WGS AF: 0.196 AC: 683 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.89
PhyloP100		0.82
Mutation Taster		=100/0	polymorphism (auto)

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: rs2237964; hg19: chr11-17532102; COSMIC: COSV50027845; COSMIC: COSV50027845;