rs77553387

Variant names:

• chr7-107674151-T-C
• rs77553387
• NM_000441.2:c.416-13T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000441.2(SLC26A4):​c.416-13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000837 in 1,609,800 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0042 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (11 hom.)
• Consequence: SLC26A4 NM_000441.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.0650
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 7-107674151-T-C is Benign according to our data. Variant chr7-107674151-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43557.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000482 (703/1457526) while in subpopulation AFR AF = 0.0162 (540/33382). AF 95% confidence interval is 0.015. There are 11 homozygotes in GnomAdExome4. There are 278 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,AD gene

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.416-13T>C		intron	N/A	NP_000432.1	O43511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.416-13T>C		intron	N/A	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.416-13T>C		intron	N/A	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.416-13T>C		intron	N/A	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.00423 AC: 644 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00109 AC: 273 AN: 251430 AF XY: 0.000773

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000482 AC: 703 AN: 1457526 Hom.: 11 Cov.: 31 AF XY: 0.000383 AC XY: 278 AN XY: 725286

African (AFR) AF: 0.0162 AC: 540 AN: 33382

American (AMR) AF: 0.000649 AC: 29 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5744

European-Non Finnish (NFE) AF: 0.0000469 AC: 52 AN: 1108320

Other (OTH) AF: 0.00118 AC: 71 AN: 60180

GnomAD4 genome AF: 0.00424 AC: 645 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.00416 AC XY: 310 AN XY: 74466

African (AFR) AF: 0.0147 AC: 611 AN: 41540

American (AMR) AF: 0.00131 AC: 20 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

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

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00295 Hom.: 1

Bravo AF: 0.00488

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.2
DANN	Benign	0.89
PhyloP100		-0.065
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs77553387; hg19: chr7-107314596;