rs146348818

Positions:

• chr7-107683285-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000441.2(SLC26A4):​c.849G>C​(p.Met283Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000581 in 1,613,354 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (5 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.52

Genes affected

SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009616643).
• BP6: Variant 7-107683285-G-C is Benign according to our data. Variant chr7-107683285-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 165247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107683285-G-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.849G>C	p.Met283Ile	missense_variant	7/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.849G>C	p.Met283Ile	missense_variant	7/21		NM_000441.2	ENSP00000494017	P1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 415 AN: 152122 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00937

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000729 AC: 183 AN: 251186 Hom.: 1 AF XY: 0.000508 AC XY: 69 AN XY: 135754

Gnomad AFR exome AF: 0.00929

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000357 AC: 521 AN: 1461114 Hom.: 5 Cov.: 31 AF XY: 0.000322 AC XY: 234 AN XY: 726910

Gnomad4 AFR exome AF: 0.00974

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152240 Hom.: 3 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74444

Gnomad4 AFR AF: 0.00936

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000435 Hom.: 0

Bravo AF: 0.00292

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000947 AC: 115

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2018	This variant is associated with the following publications: (PMID: 27771369, 30245029, 27884173, 16570074, 25262649) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Met283Ile in Exon 07 of SLC26A4: This variant is not expected to have clinical s ignificance because it has been identified in 0.9% (32/3736) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs146348818). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2022	Variant summary: SLC26A4 c.849G>C (p.Met283Ile) results in a conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00073 in 251186 control chromosomes, predominantly at a frequency of 0.0093 within the African or African-American subpopulation in the gnomAD database, including one homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC26A4 causing Pendred Syndrome phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=1) and benign (n=4). Based on the evidence outlined above, the variant was classified as benign. -

Pendred syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 14, 2017	- -

SLC26A4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	.;D
MetaRNN	Benign	0.0096	T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	-0.24	N;N
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.89	N;.
REVEL	Uncertain	0.39
Sift	Benign	0.44	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.013	B;B
Vest4		0.69
MutPred		0.81		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.92
MPC		0.018
ClinPred		0.0066	T
GERP RS		5.3
Varity_R		0.33
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs146348818; hg19: chr7-107323730;