rs145805875

Variant names:

• chr7-107710095-G-A
• rs145805875
• NM_000441.2:c.2131G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-107710095-G-A
• chr7-107710095-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP2

The NM_000441.2(SLC26A4):​c.2131G>A​(p.Asp711Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,459,284 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D711Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 5.62
• Publications: 5 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000441.2
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 4, Pendred syndrome, athyreosis, thyroid hypoplasia, hearing loss, autosomal recessive.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.2131G>A	p.Asp711Asn	missense_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.2131G>A	p.Asp711Asn	missense_variant	Exon 19 of 21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000644846.1	n.*33G>A		non_coding_transcript_exon_variant	Exon 8 of 10			ENSP00000494344.1
SLC26A4	ENST00000644846.1	n.*33G>A		3_prime_UTR_variant	Exon 8 of 10			ENSP00000494344.1
SLC26A4	ENST00000492030.2	n.377-60G>A		intron_variant	Intron 3 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459284 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 726184

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109706

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Uncertain:3

Aug 16, 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. -

Mar 20, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Aug 31, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Asp711Asn variant has not been reported in the literature nor previously ide ntified by our laboratory. This residue is well conserved across mammals and mos t vertebrates; however, it is replaced with glutamic acid in zebrafish. Computat ional analyses (amino acid properties, PolyPhen2, SIFT, AlignGVGD) provide incon sistent predictions on the impact of the variant. It should be noted that this l ab has only sequenced SLC26A4 in 44 Asian probands and no Asian healthy controls . In addition, healthy control information is limited in either public databases or scientific literature, such that the full spectrum of benign variation has n ot yet been defined for this population. Future analysis could reveal that the A sp711Asn variant is common in this population and therefore unlikely to be patho genic. In summary, the clinical significance of this variant is not clear at thi s time. -

not provided Uncertain:1

Aug 19, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1

Sep 05, 2021

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
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.7	L;L
PhyloP100		5.6
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Uncertain	0.52
Sift	Benign	0.48	T;.
Sift4G	Benign	0.078	T;.
Polyphen		1.0	D;D
Vest4		0.59
MutPred		0.43		Loss of ubiquitination at K715 (P = 0.1647);Loss of ubiquitination at K715 (P = 0.1647);
MVP		0.99
MPC		0.072
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.32
gMVP		0.55
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs145805875; hg19: chr7-107350540; COSMIC: COSV55917059;