rs1019126381

Variant names:

• chr6-31863664-T-C
• rs1019126381
• NM_025257.3:c.2096A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025257.3(SLC44A4):​c.2096A>G​(p.Asn699Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC44A4 NM_025257.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.61

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28806382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC44A4	NM_025257.3	c.2096A>G	p.Asn699Ser	missense_variant	Exon 21 of 21	ENST00000229729.11	NP_079533.2
SLC44A4	NM_001178044.2	c.1970A>G	p.Asn657Ser	missense_variant	Exon 20 of 20		NP_001171515.1
SLC44A4	NM_001178045.2	c.1868A>G	p.Asn623Ser	missense_variant	Exon 21 of 21		NP_001171516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC44A4	ENST00000229729.11	c.2096A>G	p.Asn699Ser	missense_variant	Exon 21 of 21	1	NM_025257.3	ENSP00000229729.6
SLC44A4	ENST00000375562.8	c.1970A>G	p.Asn657Ser	missense_variant	Exon 20 of 20	2		ENSP00000364712.4
SLC44A4	ENST00000544672.5	c.1868A>G	p.Asn623Ser	missense_variant	Exon 21 of 21	2		ENSP00000444109.1
SLC44A4	ENST00000487680.1	n.305A>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460140 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726396

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2096A>G (p.N699S) alteration is located in exon 21 (coding exon 21) of the SLC44A4 gene. This alteration results from a A to G substitution at nucleotide position 2096, causing the asparagine (N) at amino acid position 699 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D;N;D;.
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D;D;D;.
Sift4G	Uncertain	0.011	D;D;D;.
Polyphen		0.78	P;.;.;.
Vest4		0.26
MutPred		0.38		Loss of helix (P = 0.0033);.;.;.;
MVP		0.076
MPC		0.72
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1019126381; hg19: chr6-31831441;