rs143002265

Variant names:

• chr7-107683500-A-G
• rs143002265
• NM_000441.2:c.964A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-107683500-A-G
• chr7-107683500-A-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP4_Strong BP6

The NM_000441.2(SLC26A4):​c.964A>G​(p.Asn322Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00023 in 1,613,920 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene SLC26A4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:9
• Conservation: PhyloP100: 4.11
• Publications: 3 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: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• 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

Specifications for SLC26A4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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 hearing loss, autosomal recessive, Pendred syndrome, autosomal recessive nonsyndromic hearing loss 4, thyroid hypoplasia, athyreosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.011786133).
• BP6: Variant 7-107683500-A-G is Benign according to our data. Variant chr7-107683500-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43573.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000441.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.964A>G	p.Asn322Asp	missense	Exon 8 of 21	NP_000432.1	O43511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.964A>G	p.Asn322Asp	missense	Exon 8 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.964A>G	p.Asn322Asp	missense	Exon 7 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.964A>G	p.Asn322Asp	missense	Exon 8 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 202 AN: 152208 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000331 AC: 83 AN: 250902 AF XY: 0.000214

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000116 AC: 169 AN: 1461594 Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 79 AN XY: 727094

African (AFR) AF: 0.00409 AC: 137 AN: 33460

American (AMR) AF: 0.000403 AC: 18 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111844

Other (OTH) AF: 0.000215 AC: 13 AN: 60378

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152326 Hom.: 1 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74486

African (AFR) AF: 0.00455 AC: 189 AN: 41582

American (AMR) AF: 0.000523 AC: 8 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000471 Hom.: 0

Bravo AF: 0.00142

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	3	1	Pendred syndrome (4)
-	1	1	Autosomal recessive nonsyndromic hearing loss 4 (2)
-	-	2	not specified (2)
-	-	1	SLC26A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.31
Sift	Benign	0.16	T
Sift4G	Benign	0.31	T
Polyphen		0.076	B
Vest4		0.26
MVP		0.92
MPC		0.016
ClinPred		0.029	T
GERP RS		3.1
Varity_R		0.33
gMVP		0.74
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs143002265; hg19: chr7-107323945;