chr6-31874821-T-A

Variant names:

• chr6-31874821-T-A
• rs12661281
• NM_025257.3:c.368A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025257.3(SLC44A4):​c.368A>T​(p.Asp123Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,612,436 control chromosomes in the GnomAD database, including 16,109 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D123D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1324 hom., cov: 31)
  • Exomes 𝑓: 0.14 (14785 hom.)
• Consequence: SLC44A4 NM_025257.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.87
• Publications: 44 publications found

Genes affected

SLC44A4 (HGNC:13941): (solute carrier family 44 member 4) The protein encoded by this gene may be a sodium-dependent transmembrane transport protein involved in the uptake of choline by cholinergic neurons. Defects in this gene can cause sialidosis, a lysosomal storage disease. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

SLC44A4 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal dominant 72

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004440546).
• BP6: Variant 6-31874821-T-A is Benign according to our data. Variant chr6-31874821-T-A is described in ClinVar as Benign. ClinVar VariationId is 1266965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC44A4	NM_025257.3	c.368A>T	p.Asp123Val	missense_variant	Exon 6 of 21	ENST00000229729.11	NP_079533.2
SLC44A4	NM_001178045.2	c.140A>T	p.Asp47Val	missense_variant	Exon 6 of 21		NP_001171516.1
SLC44A4	NM_001178044.2	c.342+108A>T		intron_variant	Intron 5 of 19		NP_001171515.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC44A4	ENST00000229729.11	c.368A>T	p.Asp123Val	missense_variant	Exon 6 of 21	1	NM_025257.3	ENSP00000229729.6
SLC44A4	ENST00000414427.1	c.353A>T	p.Asp118Val	missense_variant	Exon 6 of 13	5		ENSP00000398901.1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17290 AN: 151504 Hom.: 1324 Cov.: 31

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.0879

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.108

GnomAD2 exomes AF: 0.150 AC: 37178 AN: 247650 AF XY: 0.148

Gnomad AFR exome AF: 0.0212

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.136 AC: 198331 AN: 1460814 Hom.: 14785 Cov.: 34 AF XY: 0.136 AC XY: 98785 AN XY: 726770

African (AFR) AF: 0.0187 AC: 624 AN: 33416

American (AMR) AF: 0.226 AC: 10048 AN: 44460

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6238 AN: 26058

East Asian (EAS) AF: 0.127 AC: 5028 AN: 39692

South Asian (SAS) AF: 0.0931 AC: 8023 AN: 86160

European-Finnish (FIN) AF: 0.114 AC: 6072 AN: 53366

Middle Eastern (MID) AF: 0.115 AC: 665 AN: 5766

European-Non Finnish (NFE) AF: 0.139 AC: 154328 AN: 1111564

Other (OTH) AF: 0.121 AC: 7305 AN: 60332

GnomAD4 genome AF: 0.114 AC: 17302 AN: 151622 Hom.: 1324 Cov.: 31 AF XY: 0.112 AC XY: 8305 AN XY: 74128

African (AFR) AF: 0.0242 AC: 1000 AN: 41308

American (AMR) AF: 0.173 AC: 2631 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 877 AN: 3464

East Asian (EAS) AF: 0.111 AC: 570 AN: 5142

South Asian (SAS) AF: 0.0884 AC: 423 AN: 4786

European-Finnish (FIN) AF: 0.109 AC: 1153 AN: 10530

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10204 AN: 67846

Other (OTH) AF: 0.109 AC: 229 AN: 2108

Alfa AF: 0.152 Hom.: 1357

Bravo AF: 0.116

TwinsUK AF: 0.143 AC: 529

ALSPAC AF: 0.126 AC: 485

ESP6500AA AF: 0.0288 AC: 127

ESP6500EA AF: 0.154 AC: 1322

ExAC AF: 0.147 AC: 17796

Asia WGS AF: 0.0890 AC: 313 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25629512) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.011
DANN	Benign	0.76
DEOGEN2	Benign	0.012	T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.011	N
MetaRNN	Benign	0.0044	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;.;.
PhyloP100		-2.9
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.2	N;N;.
REVEL	Benign	0.045
Sift	Benign	0.14	T;T;.
Sift4G	Benign	0.18	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.048
MPC		0.30
ClinPred		0.018	T
GERP RS		-9.7
Varity_R		0.096
gMVP		0.70
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs12661281; hg19: chr6-31842598;