rs1387758666

Variant names:

• chr7-107710169-T-G
• rs1387758666
• NM_000441.2:c.2205T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000441.2(SLC26A4):​c.2205T>G​(p.Ser735Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:2
• Conservation: PhyloP100: -0.0180
• Publications: 1 publications found

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]

SLC26A4 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Pendred syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-107710169-T-G is Benign according to our data. Variant chr7-107710169-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 551589.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.018 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.2205T>G	p.Ser735Ser	synonymous_variant	Exon 19 of 21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2205T>G	p.Ser735Ser	synonymous_variant	Exon 19 of 21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000492030.2	n.391T>G		non_coding_transcript_exon_variant	Exon 4 of 6	5
SLC26A4	ENST00000644846.1	n.*107T>G		non_coding_transcript_exon_variant	Exon 8 of 10			ENSP00000494344.1
SLC26A4	ENST00000644846.1	n.*107T>G		3_prime_UTR_variant	Exon 8 of 10			ENSP00000494344.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251276 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455106 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 724358

African (AFR) AF: 0.00 AC: 0 AN: 33328

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105870

Other (OTH) AF: 0.00 AC: 0 AN: 60160

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Pendred syndrome Uncertain:1

Apr 19, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Benign:1

Dec 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SLC26A4-related disorder Benign:1

Jun 06, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.6
DANN	Benign	0.57
PhyloP100		-0.018
Mutation Taster		=100/0	polymorphism

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: rs1387758666; hg19: chr7-107350614;