6-31878964-C-A

Position:

• chr6-31878964-C-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.17G>T​(p.Arg6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0808 in 1,613,548 control chromosomes in the GnomAD database, including 7,091 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 0.093 (815 hom., cov: 32)
  • Exomes 𝑓: 0.080 (6276 hom.)
• Consequence: SLC44A4 NM_025257.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.853

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]

EHMT2-AS1 (HGNC:39751): (EHMT2 and SLC44A4 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.248223E-4).
• BP6: Variant 6-31878964-C-A is Benign according to our data. Variant chr6-31878964-C-A is described in ClinVar as [Benign]. Clinvar id is 1283506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC44A4	NM_025257.3	c.17G>T	p.Arg6Leu	missense_variant	1/21	ENST00000229729.11
EHMT2-AS1	NR_174947.1	n.271+886C>A		intron_variant, non_coding_transcript_variant
SLC44A4	NM_001178044.2	c.17G>T	p.Arg6Leu	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC44A4	ENST00000229729.11	c.17G>T	p.Arg6Leu	missense_variant	1/21	1	NM_025257.3	P1
EHMT2-AS1	ENST00000642849.1	n.271+886C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0924 AC: 14057 AN: 152062 Hom.: 816 Cov.: 32

Gnomad AFR AF: 0.0807

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0694

Gnomad OTH AF: 0.0839

GnomAD3 exomes AF: 0.108 AC: 27062 AN: 250636 Hom.: 1977 AF XY: 0.104 AC XY: 14049 AN XY: 135532

Gnomad AFR exome AF: 0.0824

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.0232

Gnomad EAS exome AF: 0.112

Gnomad SAS exome AF: 0.127

Gnomad FIN exome AF: 0.174

Gnomad NFE exome AF: 0.0694

Gnomad OTH exome AF: 0.0966

GnomAD4 exome AF: 0.0796 AC: 116370 AN: 1461368 Hom.: 6276 Cov.: 33 AF XY: 0.0800 AC XY: 58171 AN XY: 726994

Gnomad4 AFR exome AF: 0.0759

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.0260

Gnomad4 EAS exome AF: 0.182

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.0650

Gnomad4 OTH exome AF: 0.0809

GnomAD4 genome AF: 0.0925 AC: 14078 AN: 152180 Hom.: 815 Cov.: 32 AF XY: 0.0991 AC XY: 7372 AN XY: 74404

Gnomad4 AFR AF: 0.0808

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.123

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.179

Gnomad4 NFE AF: 0.0693

Gnomad4 OTH AF: 0.0835

Alfa AF: 0.0669 Hom.: 707

Bravo AF: 0.0917

TwinsUK AF: 0.0615 AC: 228

ALSPAC AF: 0.0659 AC: 254

ESP6500AA AF: 0.0783 AC: 345

ESP6500EA AF: 0.0657 AC: 565

ExAC AF: 0.103 AC: 12487

EpiCase AF: 0.0632

EpiControl AF: 0.0614

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 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.16
DANN	Benign	0.84
DEOGEN2	Benign	0.0083	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.014	N
MetaRNN	Benign	0.00072	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.019
Sift	Benign	0.10	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0020	B;.
Vest4		0.074
MPC		0.26
ClinPred		0.011	T
GERP RS		-3.2
Varity_R		0.077
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: rs2075798; hg19: chr6-31846741; COSMIC: COSV57666987; COSMIC: COSV57666987;