rs959216005

Variant names:

• chr7-107704343-T-G
• rs959216005
• NM_000441.2:c.2047T>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000441.2(SLC26A4):​c.2047T>G​(p.Phe683Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F683S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.72
• Publications: 0 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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107704344-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 402277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

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.2047T>G	p.Phe683Val	missense	Exon 18 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.2047T>G	p.Phe683Val	missense	Exon 18 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.2047T>G	p.Phe683Val	missense	Exon 17 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1969T>G	p.Phe657Val	missense	Exon 17 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.75
MutPred		0.77		Loss of MoRF binding (P = 0.1165)
MVP		0.98
MPC		0.069
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.78
Mutation Taster		=7/93	disease causing

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: rs959216005; hg19: chr7-107344788;