rs2242665

Positions:

• chr6-31871532-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025257.3(SLC44A4):​c.559G>A​(p.Val187Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,611,384 control chromosomes in the GnomAD database, including 260,629 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.60 (27739 hom., cov: 30)
  • Exomes 𝑓: 0.56 (232890 hom.)
• Consequence: SLC44A4 NM_025257.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.113

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7938253E-6).
• BP6: Variant 6-31871532-C-T is Benign according to our data. Variant chr6-31871532-C-T is described in ClinVar as [Benign]. Clinvar id is 1224894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC44A4	NM_025257.3	c.559G>A	p.Val187Ile	missense_variant	8/21	ENST00000229729.11	NP_079533.2
SLC44A4	NM_001178044.2	c.433G>A	p.Val145Ile	missense_variant	7/20		NP_001171515.1
SLC44A4	NM_001178045.2	c.331G>A	p.Val111Ile	missense_variant	8/21		NP_001171516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC44A4	ENST00000229729.11	c.559G>A	p.Val187Ile	missense_variant	8/21	1	NM_025257.3	ENSP00000229729.6
SLC44A4	ENST00000414427.1	c.544G>A	p.Val182Ile	missense_variant	8/13	5		ENSP00000398901.1
SLC44A4	ENST00000375562.8	c.433G>A	p.Val145Ile	missense_variant	7/20	2		ENSP00000364712.4
SLC44A4	ENST00000544672.5	c.331G>A	p.Val111Ile	missense_variant	8/21	2		ENSP00000444109.1

Frequencies

GnomAD3 genomes AF: 0.599 AC: 90739 AN: 151590 Hom.: 27710 Cov.: 30

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.579

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.598

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.557

Gnomad OTH AF: 0.660

GnomAD3 exomes AF: 0.597 AC: 149871 AN: 250964 Hom.: 45860 AF XY: 0.599 AC XY: 81268 AN XY: 135628

Gnomad AFR exome AF: 0.670

Gnomad AMR exome AF: 0.646

Gnomad ASJ exome AF: 0.816

Gnomad EAS exome AF: 0.609

Gnomad SAS exome AF: 0.619

Gnomad FIN exome AF: 0.438

Gnomad NFE exome AF: 0.574

Gnomad OTH exome AF: 0.614

GnomAD4 exome AF: 0.560 AC: 816789 AN: 1459676 Hom.: 232890 Cov.: 57 AF XY: 0.564 AC XY: 409711 AN XY: 726240

Gnomad4 AFR exome AF: 0.676

Gnomad4 AMR exome AF: 0.649

Gnomad4 ASJ exome AF: 0.810

Gnomad4 EAS exome AF: 0.630

Gnomad4 SAS exome AF: 0.621

Gnomad4 FIN exome AF: 0.432

Gnomad4 NFE exome AF: 0.543

Gnomad4 OTH exome AF: 0.580

GnomAD4 genome AF: 0.599 AC: 90828 AN: 151708 Hom.: 27739 Cov.: 30 AF XY: 0.595 AC XY: 44092 AN XY: 74116

Gnomad4 AFR AF: 0.671

Gnomad4 AMR AF: 0.642

Gnomad4 ASJ AF: 0.811

Gnomad4 EAS AF: 0.598

Gnomad4 SAS AF: 0.605

Gnomad4 FIN AF: 0.429

Gnomad4 NFE AF: 0.557

Gnomad4 OTH AF: 0.662

Alfa AF: 0.587 Hom.: 49544

Bravo AF: 0.621

TwinsUK AF: 0.544 AC: 2016

ALSPAC AF: 0.545 AC: 2100

ESP6500AA AF: 0.661 AC: 2911

ESP6500EA AF: 0.558 AC: 4800

ExAC AF: 0.598 AC: 72561

Asia WGS AF: 0.601 AC: 2095 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Hearing loss, autosomal dominant 72 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.16
DANN	Benign	0.59
DEOGEN2	Benign	0.0037	T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0020	N
MetaRNN	Benign	0.0000018	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.23	N;N;N;.
REVEL	Benign	0.0090
Sift	Benign	0.45	T;T;T;.
Sift4G	Benign	0.74	T;T;T;.
Polyphen		0.0	B;.;.;.
Vest4		0.020
MPC		0.17
ClinPred		0.0069	T
GERP RS		0.52
Varity_R		0.015
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2242665; hg19: chr6-31839309; COSMIC: COSV57666266; COSMIC: COSV57666266;