chr7-107661643-T-C

Variant names:

• chr7-107661643-T-C
• rs111033302
• NM_000441.2:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,562,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 2.90
• Publications: 11 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-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 10 pathogenic variants. Next in-frame start position is after 21 codons. Genomic position: 107661702. Lost 0.026 part of the original CDS.
• PS1: Another start lost variant in NM_000441.2 (SLC26A4) was described as [Likely_pathogenic] in ClinVar
• PP5: Variant 7-107661643-T-C is Pathogenic according to our data. Variant chr7-107661643-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 43553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2T>C	p.Met1?	start_lost	Exon 2 of 21	NP_000432.1	O43511-1
	SLC26A4-AS1	NR_028137.1		n.156A>G		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 2 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.2T>C	p.Met1?	start_lost	Exon 2 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152258 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000694 AC: 12 AN: 172798 AF XY: 0.0000846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000152 AC: 214 AN: 1410366 Hom.: 0 Cov.: 30 AF XY: 0.000129 AC XY: 90 AN XY: 698144

African (AFR) AF: 0.00 AC: 0 AN: 32658

American (AMR) AF: 0.0000260 AC: 1 AN: 38430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25416

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37702

South Asian (SAS) AF: 0.00 AC: 0 AN: 80854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.000190 AC: 207 AN: 1091652

Other (OTH) AF: 0.0000850 AC: 5 AN: 58824

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74394

African (AFR) AF: 0.0000482 AC: 2 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000168 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000260 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Autosomal recessive nonsyndromic hearing loss 4 (4)
4	-	-	Pendred syndrome (4)
2	-	-	SLC26A4-related disorder (2)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.23	D
PhyloP100		2.9
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.089	B
Vest4		0.94
MVP		0.97
ClinPred		0.58	D
GERP RS		3.8
Varity_R		0.56
gMVP		0.57
Mutation Taster		=12/188	disease causing (ClinVar)

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: rs111033302; hg19: chr7-107302088;