rs727503446

Variant names:

• chr15-43610989-A-C
• rs727503446
• NM_153700.2:c.3307-5T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_153700.2(STRC):​c.3307-5T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 121,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 21)
  • Exomes 𝑓: 0.000086 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STRC NM_153700.2 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.260

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRC	NM_153700.2	c.3307-5T>G		splice_region_variant, intron_variant	Intron 13 of 28	ENST00000450892.7	NP_714544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRC	ENST00000450892.7	c.3307-5T>G		splice_region_variant, intron_variant	Intron 13 of 28	5	NM_153700.2	ENSP00000401513.2

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 16 AN: 121242 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000820

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00410

Gnomad NFE AF: 0.0000671

Gnomad OTH AF: 0.000615

GnomAD2 exomes AF: 0.000124 AC: 31 AN: 250930 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000856 AC: 120 AN: 1401402 Hom.: 0 Cov.: 30 AF XY: 0.0000830 AC XY: 58 AN XY: 699126

Gnomad4 AFR exome AF: 0.0000335 AC: 1 AN: 29818

Gnomad4 AMR exome AF: 0.000634 AC: 28 AN: 44172

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 24838

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 38530

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 84842

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53150

Gnomad4 NFE exome AF: 0.0000743 AC: 79 AN: 1062808

Gnomad4 Remaining exome AF: 0.000156 AC: 9 AN: 57740

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000132 AC: 16 AN: 121334 Hom.: 0 Cov.: 21 AF XY: 0.000135 AC XY: 8 AN XY: 59258

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.000819 AC: 0.000818599 AN: 0.000818599

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000671 AC: 0.0000670803 AN: 0.0000670803

Gnomad4 OTH AF: 0.000611 AC: 0.000610501 AN: 0.000610501

Alfa AF: 0.0000480 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Nov 19, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The 3307-5T>G v ariant in STRC has not been previously reported in individuals with hearing loss or in large population studies. This variant is located in the 3' splice region and diverges from the semi-conserved -5 position within splice site consensus s equence. In addition, computational tools suggest that the variant may lead to a bnormal splicing. However, this information is not predictive enough to determin e pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty; however based upon the conservation and computationa l data, we would lean towards a more likely pathogenic role. -

not provided Uncertain:1

Mar 16, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge -

Autosomal recessive nonsyndromic hearing loss 16 Uncertain:1

-

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.54		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503446; hg19: chr15-43903187;