rs12661281

Positions:

• chr6-31874821-T-A

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.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. 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 same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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=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 id 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/exons	MANE	Protein	UniProt
SLC44A4	NM_025257.3	c.368A>T	p.Asp123Val	missense_variant	6/21	ENST00000229729.11	NP_079533.2
SLC44A4	NM_001178045.2	c.140A>T	p.Asp47Val	missense_variant	6/21		NP_001171516.1
SLC44A4	NM_001178044.2	c.342+108A>T		intron_variant			NP_001171515.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC44A4	ENST00000229729.11	c.368A>T	p.Asp123Val	missense_variant	6/21	1	NM_025257.3	ENSP00000229729	P1

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

GnomAD3 exomes AF: 0.150 AC: 37178 AN: 247650 Hom.: 3267 AF XY: 0.148 AC XY: 19852 AN XY: 133960

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 SAS exome AF: 0.0963

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

Gnomad4 AFR exome AF: 0.0187

Gnomad4 AMR exome AF: 0.226

Gnomad4 ASJ exome AF: 0.239

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.0931

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.121

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

Gnomad4 AFR AF: 0.0242

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.253

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.0884

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.109

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	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;.;.
MutationTaster	Benign	1.0	P;P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs12661281; hg19: chr6-31842598;