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

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACGS-UK Somatic Oncogenicity v2025).

The NM_000441.2(SLC26A4):c.1001+1G>A 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 gene SLC26A4 is a known oncogene (CancerMine: 2 oncogene citations). The variant allele was found at a cumulative frequency of 0.000282 (AC=454) in the gnomAD database across 1,612,484 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000331. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). The variant has been observed in cBioPortal in 1 sample across 1 study and 1 cancer type; somatic enrichment level: NONE (Observed in at most one deduplicated cBioPortal case.).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:30 O:2
• Conservation: PhyloP100: 6.97
• Publications: 46 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 ACGS-UK Somatic Oncogenicity v2025

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: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
No applied criteria Uncheck "Show applied only" above to review all 20 criteria.

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>A	splice_donorintron	Intron 8 of 20	Prot: NP_000432.1 UniProt:

SLC26A4 NM_000441.2

MANE Select

HGVSc / HGVSpc.1001+1G>A

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>A	splice_donorintron	Intron 8 of 20	Prot: ENSP00000494017.1 UniProt:
	SLC26A4 ENST00000888701.1		c.1001+1G>A	splice_donorintron	Intron 7 of 19	Prot: ENSP00000558760.1 UniProt:
	SLC26A4 ENST00000888700.1		c.1001+1G>A	splice_donorintron	Intron 8 of 19	Prot: ENSP00000558759.1 UniProt:

SLC26A4 ENST00000644269.2

MANE Select

HGVSc / HGVSpc.1001+1G>A

Exon rankIntron 8 of 20

splice_donorintron

Prot: ENSP00000494017.1UniProt: O43511-1

SLC26A4 ENST00000888701.1

HGVSc / HGVSpc.1001+1G>A

Exon rankIntron 7 of 19

splice_donorintron

Prot: ENSP00000558760.1UniProt: O43511-1

SLC26A4 ENST00000888700.1

HGVSc / HGVSpc.1001+1G>A

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000223	AC:34	Hom:0	AN:152158	Cov:32
GnomAD2 exomes	AF: 0.000196	AC:49	Hom:	AN:250282	Cov:
GnomAD4 exome	AF: 0.000288	AC:420	Hom:0	AN:1460326	Cov:30
GnomAD4 genome	AF: 0.000223	AC:34	Hom:0	AN:152158	Cov:32
TOPMed (Bravo)	AF: 0.000242	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000339	AC:158	Hom:0	AN:466006	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.000461	AC:6	Hom:	AN:13006	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000570	AC:7	Hom:0	AN:122390	Cov:
UK10K	AF: 0.000264	AC:2	Hom:	AN:7562	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000540 *	6	11110	0.000568 *	10	17608
BipEx(Bipolar disorder (including schizoaffective))	0.000317	9	28420	0.000312	9	28844
SCHEMA(Schizophrenia)	0.000246	30	121782	0.000184	35	190612

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	not provided (9)
9	-	-	Pendred syndrome (10)
6	-	-	Autosomal recessive nonsyndromic hearing loss 4 (6)
2	-	-	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (2)
2	-	-	SLC26A4-related disorder (3)
1	-	-	Monogenic hearing loss (1)
1	-	-	Rare genetic deafness (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.39
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	-9.8
GPN-Star score	N/A	9.8
Mutation Taster	N/A	6/94	disease causing (ClinVar)
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	0.78	Position offset: 39
DS_DL_spliceai	Pathogenic	0.99	Position offset: -1
Pangolin (max)	Pathogenic	0.86
Pangolin gain	Pathogenic	0.64	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