rs55843567

Variant names:

• chr11-17527331-C-T
• rs55843567
• NM_153676.4:c.388G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-17527331-C-T
• chr11-17527331-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153676.4(USH1C):​c.388G>A​(p.Val130Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,610,172 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V130A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (41 hom., cov: 30)
  • Exomes 𝑓: 0.0012 (35 hom.)
• Consequence: USH1C NM_153676.4 missense, splice_region
• Scores: Splicing: ADA: 0.9074
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 2.04
• 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=0.010829568).
• BP6: Variant 11-17527331-C-T is Benign according to our data. Variant chr11-17527331-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 5149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1903/151900) while in subpopulation AFR AF = 0.0444 (1840/41416). AF 95% confidence interval is 0.0427. There are 41 homozygotes in GnomAd4. There are 866 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 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.388G>A	p.Val130Ile	missense splice_region	Exon 5 of 27	NP_710142.1	Q9Y6N9-5
	USH1C	NM_005709.4	MANE Plus Clinical	c.388G>A	p.Val130Ile	missense splice_region	Exon 5 of 21	NP_005700.2	A0A0S2Z4U9
	USH1C	NM_001440679.1		c.421G>A	p.Val141Ile	missense splice_region	Exon 5 of 22	NP_001427608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH1C	ENST00000005226.12	TSL:5 MANE Select	c.388G>A	p.Val130Ile	missense splice_region	Exon 5 of 27	ENSP00000005226.7	Q9Y6N9-5
	USH1C	ENST00000318024.9	TSL:1 MANE Plus Clinical	c.388G>A	p.Val130Ile	missense splice_region	Exon 5 of 21	ENSP00000317018.4	Q9Y6N9-1
	USH1C	ENST00000527020.5	TSL:1	c.388G>A	p.Val130Ile	missense splice_region	Exon 5 of 20	ENSP00000436934.1	Q9Y6N9-4

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1903 AN: 151782 Hom.: 41 Cov.: 30

Gnomad AFR AF: 0.0446

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

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: 0.0000589

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00317 AC: 790 AN: 248928 AF XY: 0.00228

Gnomad AFR exome AF: 0.0447

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00120 AC: 1743 AN: 1458272 Hom.: 35 Cov.: 32 AF XY: 0.00103 AC XY: 750 AN XY: 725640

African (AFR) AF: 0.0445 AC: 1488 AN: 33466

American (AMR) AF: 0.00150 AC: 67 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50478

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5750

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111452

Other (OTH) AF: 0.00249 AC: 150 AN: 60342

GnomAD4 genome AF: 0.0125 AC: 1903 AN: 151900 Hom.: 41 Cov.: 30 AF XY: 0.0117 AC XY: 866 AN XY: 74234

African (AFR) AF: 0.0444 AC: 1840 AN: 41416

American (AMR) AF: 0.00347 AC: 53 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67938

Other (OTH) AF: 0.00285 AC: 6 AN: 2104

Alfa AF: 0.00427 Hom.: 32

Bravo AF: 0.0146

ESP6500AA AF: 0.0441 AC: 194

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00406 AC: 493

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	1	2	Usher syndrome type 1C (3)
-	-	1	Usher syndrome type 1;C1848604:Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.063
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.0
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.036
Sift	Benign	0.27	T
Sift4G	Benign	0.43	T
Polyphen		0.0030	B
Vest4		0.39
MVP		0.51
MPC		0.060
ClinPred		0.0097	T
GERP RS		3.1
Varity_R		0.11
gMVP		0.35
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Benign	0.63
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55843567; hg19: chr11-17548878; COSMIC: COSV105836118;