rs3097773

Variant names:

• chr15-43600874-G-A
• rs3097773
• NM_153700.2:c.4842C>T

Variant summary

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

The NM_153700.2(STRC):​c.4842C>T​(p.Phe1614Phe) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,608,376 control chromosomes in the GnomAD database, including 35,608 homozygotes. In-silico tool predicts 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (11393 hom., cov: 27)
  • Exomes 𝑓: 0.13 (24215 hom.)
• Consequence: STRC NM_153700.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.2833
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.57
• Publications: 21 publications found

Genes affected

STRC (HGNC:16035): (stereocilin) This gene encodes a protein that is associated with the hair bundle of the sensory hair cells in the inner ear. The hair bundle is composed of stiff microvilli called stereocilia and is involved with mechanoreception of sound waves. This gene is part of a tandem duplication on chromosome 15; the second copy is a pseudogene. Mutations in this gene cause autosomal recessive non-syndromic deafness. [provided by RefSeq, Jul 2008]

CKMT1B (HGNC:1995): (creatine kinase, mitochondrial 1B) Mitochondrial creatine (MtCK) kinase is responsible for the transfer of high energy phosphate from mitochondria to the cytosolic carrier, creatine. It belongs to the creatine kinase isoenzyme family. It exists as two isoenzymes, sarcomeric MtCK and ubiquitous MtCK, encoded by separate genes. Mitochondrial creatine kinase occurs in two different oligomeric forms: dimers and octamers, in contrast to the exclusively dimeric cytosolic creatine kinase isoenzymes. Many malignant cancers with poor prognosis have shown overexpression of ubiquitous mitochondrial creatine kinase; this may be related to high energy turnover and failure to eliminate cancer cells via apoptosis. Ubiquitous mitochondrial creatine kinase has 80% homology with the coding exons of sarcomeric mitochondrial creatine kinase. Two genes located near each other on chromosome 15 have been identified which encode identical mitochondrial creatine kinase proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 15-43600874-G-A is Benign according to our data. Variant chr15-43600874-G-A is described in ClinVar as [Benign]. Clinvar id is 177982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2	c.4842C>T	p.Phe1614Phe	splice_region_variant, synonymous_variant	Exon 25 of 29	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.4842C>T	p.Phe1614Phe	splice_region_variant, synonymous_variant	Exon 25 of 29	5	NM_153700.2	ENSP00000401513.2

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43416 AN: 150938 Hom.: 11362 Cov.: 27

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.0784

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.0980

Gnomad OTH AF: 0.243

GnomAD2 exomes AF: 0.195 AC: 48896 AN: 250948 AF XY: 0.183

Gnomad AFR exome AF: 0.698

Gnomad AMR exome AF: 0.216

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.440

Gnomad FIN exome AF: 0.0753

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.135 AC: 196190 AN: 1457324 Hom.: 24215 Cov.: 34 AF XY: 0.135 AC XY: 97757 AN XY: 725142

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.717 AC: 23901 AN: 33332

American (AMR) AF: 0.213 AC: 9501 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 5039 AN: 26100

East Asian (EAS) AF: 0.431 AC: 17100 AN: 39648

South Asian (SAS) AF: 0.195 AC: 16774 AN: 85924

European-Finnish (FIN) AF: 0.0763 AC: 4071 AN: 53390

Middle Eastern (MID) AF: 0.154 AC: 885 AN: 5746

European-Non Finnish (NFE) AF: 0.0979 AC: 108515 AN: 1108354

Other (OTH) AF: 0.173 AC: 10404 AN: 60186

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.288 AC: 43500 AN: 151052 Hom.: 11393 Cov.: 27 AF XY: 0.284 AC XY: 20912 AN XY: 73714

African (AFR) AF: 0.688 AC: 28159 AN: 40900

American (AMR) AF: 0.222 AC: 3366 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 651 AN: 3460

East Asian (EAS) AF: 0.422 AC: 2163 AN: 5122

South Asian (SAS) AF: 0.214 AC: 1018 AN: 4768

European-Finnish (FIN) AF: 0.0784 AC: 822 AN: 10486

Middle Eastern (MID) AF: 0.209 AC: 61 AN: 292

European-Non Finnish (NFE) AF: 0.0980 AC: 6646 AN: 67830

Other (OTH) AF: 0.247 AC: 517 AN: 2094

Alfa AF: 0.175 Hom.: 1680

Bravo AF: 0.322

Asia WGS AF: 0.350 AC: 1214 AN: 3478

EpiCase AF: 0.112

EpiControl AF: 0.112

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 26, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Phe1614Phe in Exon 25 of STRC: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, has been identified in 68% (2942/4400) of Africa n American chromosomes from a broad population by the NHBLI Exon sequencing proj ect (http://evs.gs.washington.edu/EVS/; dbSNP rs3097773). -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive nonsyndromic hearing loss 16 Benign:1

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Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.80
PhyloP100		1.6
Mutation Taster		=17/83	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.28
dbscSNV1_RF	Benign	0.56
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.40		Position offset: -2

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

Other links and lift over

dbSNP: rs3097773; hg19: chr15-43893072; COSMIC: COSV55851798; COSMIC: COSV55851798;