chr7-103377569-A-G

Variant names:

• chr7-103377569-A-G
• rs10273883
• NM_198999.3:c.1986+30T>C

Variant summary

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

The NM_198999.3(SLC26A5):​c.1986+30T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,602,314 control chromosomes in the GnomAD database, including 782,826 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (67096 hom., cov: 31)
  • Exomes 𝑓: 0.99 (715730 hom.)
• Consequence: SLC26A5 NM_198999.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0740
• Publications: 7 publications found

Genes affected

SLC26A5 (HGNC:9359): (solute carrier family 26 member 5) This gene encodes a member of the SLC26A/SulP transporter family. The protein functions as a molecular motor in motile outer hair cells (OHCs) of the cochlea, inducing changes in cell length that act to amplify sound levels. The transmembrane protein is an incomplete anion transporter, and does not allow anions to cross the cell membrane but instead undergoes a conformational change in response to changes in intracellular Cl- levels that results in a change in cell length. The protein functions at microsecond rates, which is several orders of magnitude faster than conventional molecular motor proteins. Mutations in this gene are potential candidates for causing neurosensory deafness. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]

SLC26A5 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 61

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, 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 (BayesDel_noAF=-0.83).
• BP6: Variant 7-103377569-A-G is Benign according to our data. Variant chr7-103377569-A-G is described in ClinVar as Benign. ClinVar VariationId is 1235817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A5	NM_198999.3	c.1986+30T>C		intron_variant	Intron 18 of 19	ENST00000306312.8	NP_945350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A5	ENST00000306312.8	c.1986+30T>C		intron_variant	Intron 18 of 19	1	NM_198999.3	ENSP00000304783.3
SLC26A5	ENST00000393727.5	c.1992+30T>C		intron_variant	Intron 16 of 17	1		ENSP00000377328.1
SLC26A5	ENST00000393723.2	c.1896+30T>C		intron_variant	Intron 15 of 16	1		ENSP00000377324.1

Frequencies

GnomAD3 genomes AF: 0.934 AC: 142032 AN: 152110 Hom.: 67062 Cov.: 31

Gnomad AFR AF: 0.771

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.973

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.952

GnomAD2 exomes AF: 0.982 AC: 246603 AN: 251042 AF XY: 0.987

Gnomad AFR exome AF: 0.765

Gnomad AMR exome AF: 0.986

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.991

GnomAD4 exome AF: 0.993 AC: 1439770 AN: 1450086 Hom.: 715730 Cov.: 28 AF XY: 0.994 AC XY: 717823 AN XY: 722228

African (AFR) AF: 0.762 AC: 25274 AN: 33178

American (AMR) AF: 0.984 AC: 44006 AN: 44702

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26069 AN: 26070

East Asian (EAS) AF: 1.00 AC: 39633 AN: 39634

South Asian (SAS) AF: 1.00 AC: 85896 AN: 85936

European-Finnish (FIN) AF: 1.00 AC: 53321 AN: 53322

Middle Eastern (MID) AF: 0.986 AC: 5641 AN: 5720

European-Non Finnish (NFE) AF: 0.999 AC: 1100908 AN: 1101496

Other (OTH) AF: 0.983 AC: 59022 AN: 60028

GnomAD4 genome AF: 0.934 AC: 142126 AN: 152228 Hom.: 67096 Cov.: 31 AF XY: 0.936 AC XY: 69680 AN XY: 74420

African (AFR) AF: 0.771 AC: 31957 AN: 41470

American (AMR) AF: 0.973 AC: 14884 AN: 15300

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5188 AN: 5188

South Asian (SAS) AF: 0.999 AC: 4812 AN: 4816

European-Finnish (FIN) AF: 1.00 AC: 10622 AN: 10622

Middle Eastern (MID) AF: 0.990 AC: 291 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67974 AN: 68040

Other (OTH) AF: 0.953 AC: 2014 AN: 2114

Alfa AF: 0.978 Hom.: 128103

Bravo AF: 0.923

Asia WGS AF: 0.985 AC: 3424 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive nonsyndromic hearing loss 61 Benign:1

Jul 15, 2021

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	-0.83
CADD	Benign	1.7
DANN	Benign	0.48
PhyloP100		-0.074
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: rs10273883; hg19: chr7-103018016;