NM_000441.2:c.1001+1G>C

Variant names:

• chr7-107683538-G-C
• rs80338849
• NM_000441.2:c.1001+1G>C

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Moderate

The NM_000441.2(SLC26A4):c.1001+1G>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC26A4 NM_000441.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.97
• Publications: 28 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: Natera, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• 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

Classification according to ACMG Germline Pathogenicity v2019

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

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Splice site frameshift, NMD predicted, LoF disease mechanism — very strong (PVS1); Splice donor variant predicted to cause a frameshift, triggering NMD. Loss of function is a known disease mechanism for this gene.
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00131) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 star(s).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SLC26A4 NM_000441.2	MANE Select	c.1001+1G>C	splice_donorintron	Intron 8 of 20	Prot: NP_000432.1 UniProt:

SLC26A4 NM_000441.2

MANE Select

HGVSc / HGVSpc.1001+1G>C

Exon rankIntron 8 of 20

splice_donorintron

Prot: NP_000432.1UniProt: O43511-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SLC26A4 ENST00000644269.2	MANE Select	c.1001+1G>C	splice_donorintron	Intron 8 of 20	Prot: ENSP00000494017.1 UniProt:
	SLC26A4 ENST00000888701.1		c.1001+1G>C	splice_donorintron	Intron 7 of 19	Prot: ENSP00000558760.1 UniProt:
	SLC26A4 ENST00000888700.1		c.1001+1G>C	splice_donorintron	Intron 8 of 19	Prot: ENSP00000558759.1 UniProt:

SLC26A4 ENST00000644269.2

MANE Select

HGVSc / HGVSpc.1001+1G>C

Exon rankIntron 8 of 20

splice_donorintron

Prot: ENSP00000494017.1UniProt: O43511-1

SLC26A4 ENST00000888701.1

HGVSc / HGVSpc.1001+1G>C

Exon rankIntron 7 of 19

splice_donorintron

Prot: ENSP00000558760.1UniProt: O43511-1

SLC26A4 ENST00000888700.1

HGVSc / HGVSpc.1001+1G>C

Exon rankIntron 8 of 19

splice_donorintron

Prot: ENSP00000558759.1UniProt: A0ACI8QA40

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
Mutation Taster	N/A	6/94	disease causing
PhyloP100	Uncertain	7.0

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
DS_DG_spliceai	Pathogenic	0.75	Position offset: 39
DS_DL_spliceai	Pathogenic	0.99	Position offset: -1
Pangolin (max)	Pathogenic	0.86
Pangolin gain	Pathogenic	0.60	Position offset: 39
Pangolin loss	Pathogenic	0.86	Position offset: -1
SpliceAI score (max)	Pathogenic	0.99	Details are displayed if max score is > 0.2

Showing 8 of 8 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs80338849;

hg19: chr7-107323983;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar