chr6-31863701-T-C

Position:

• chr6-31863701-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_025257.3(SLC44A4):​c.2059A>G​(p.Met687Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,612,400 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: SLC44A4 NM_025257.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.54

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08819413).
• BP6: Variant 6-31863701-T-C is Benign according to our data. Variant chr6-31863701-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2212653.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC44A4	NM_025257.3	c.2059A>G	p.Met687Val	missense_variant	21/21	ENST00000229729.11	NP_079533.2
SLC44A4	NM_001178044.2	c.1933A>G	p.Met645Val	missense_variant	20/20		NP_001171515.1
SLC44A4	NM_001178045.2	c.1831A>G	p.Met611Val	missense_variant	21/21		NP_001171516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC44A4	ENST00000229729.11	c.2059A>G	p.Met687Val	missense_variant	21/21	1	NM_025257.3	ENSP00000229729	P1
SLC44A4	ENST00000375562.8	c.1933A>G	p.Met645Val	missense_variant	20/20	2		ENSP00000364712
SLC44A4	ENST00000544672.5	c.1831A>G	p.Met611Val	missense_variant	21/21	2		ENSP00000444109
SLC44A4	ENST00000487680.1	n.268A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.000441 AC: 67 AN: 151952 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000172 AC: 42 AN: 244810 Hom.: 0 AF XY: 0.000142 AC XY: 19 AN XY: 133626

Gnomad AFR exome AF: 0.00126

Gnomad AMR exome AF: 0.000467

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000458

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.0000746 AC: 109 AN: 1460330 Hom.: 0 Cov.: 31 AF XY: 0.0000716 AC XY: 52 AN XY: 726484

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000382

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152070 Hom.: 0 Cov.: 31 AF XY: 0.000484 AC XY: 36 AN XY: 74328

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000717 Hom.: 0

Bravo AF: 0.000495

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00232 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000187 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.2059A>G (p.M687V) 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 2059, causing the methionine (M) at amino acid position 687 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.088	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D;N;D;.
REVEL	Uncertain	0.41
Sift	Benign	0.14	T;T;T;.
Sift4G	Uncertain	0.039	D;D;D;.
Polyphen		0.95	P;.;.;.
Vest4		0.74
MVP		0.22
MPC		0.67
ClinPred		0.084	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.70
gMVP		0.94

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: rs150385253; hg19: chr6-31831478;