7-107696048-C-T

Variant names:

• chr7-107696048-C-T
• rs368970459
• NM_000441.2:c.1544+9C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000441.2(SLC26A4):​c.1544+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,454,764 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts 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 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (17 hom.)
• Consequence: SLC26A4 NM_000441.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.381
• Publications: 6 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 7-107696048-C-T is Benign according to our data. Variant chr7-107696048-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165255.
• BS2: High Homozygotes in GnomAdExome4 at 17 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.1544+9C>T		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.1544+9C>T		intron	N/A	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.1544+9C>T		intron	N/A	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1466+9C>T		intron	N/A	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.000632 AC: 96 AN: 152008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00187 AC: 470 AN: 251208 AF XY: 0.00247

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00117 AC: 1519 AN: 1302638 Hom.: 17 Cov.: 20 AF XY: 0.00158 AC XY: 1037 AN XY: 656582

African (AFR) AF: 0.000231 AC: 7 AN: 30298

American (AMR) AF: 0.000157 AC: 7 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.0000795 AC: 2 AN: 25142

East Asian (EAS) AF: 0.0000514 AC: 2 AN: 38890

South Asian (SAS) AF: 0.0132 AC: 1098 AN: 83140

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53358

Middle Eastern (MID) AF: 0.00276 AC: 15 AN: 5434

European-Non Finnish (NFE) AF: 0.000320 AC: 309 AN: 966818

Other (OTH) AF: 0.00125 AC: 69 AN: 55050

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000834 AC XY: 62 AN XY: 74360

African (AFR) AF: 0.0000723 AC: 3 AN: 41512

American (AMR) AF: 0.000459 AC: 7 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0125 AC: 60 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68002

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.000748 Hom.: 2

Bravo AF: 0.000348

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	2	Pendred syndrome (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.5
DANN	Benign	0.76
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs368970459; hg19: chr7-107336493;