3-126006524-C-A

Position:

• chr3-126006524-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001008485.2(SLC41A3):​c.1407G>T​(p.Arg469Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC41A3 NM_001008485.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.951

Genes affected

SLC41A3 (HGNC:31046): (solute carrier family 41 member 3) Predicted to enable cation transmembrane transporter activity. Predicted to be involved in cation transmembrane transport. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC41A3 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050858587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC41A3	NM_017836.4	c.*492G>T		3_prime_UTR_variant	11/11	ENST00000360370.9	NP_060306.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC41A3	ENST00000360370.9	c.*492G>T		3_prime_UTR_variant	11/11	1	NM_017836.4	ENSP00000353533.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460548 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726572

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: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2023

The c.1407G>T (p.R469S) alteration is located in exon 12 (coding exon 11) of the SLC41A3 gene. This alteration results from a G to T substitution at nucleotide position 1407, causing the arginine (R) at amino acid position 469 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	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.3
DANN	Benign	0.90
DEOGEN2	Benign	0.00050	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.051	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.49	N;N
REVEL	Benign	0.045
Sift	Uncertain	0.0080	D;T
Sift4G	Benign	0.096	T;T
Polyphen		0.0	B;B
Vest4		0.14
MutPred		0.28		.;Gain of disorder (P = 0.0615);
MVP		0.12
MPC		0.17
ClinPred		0.079	T
GERP RS		0.97
Varity_R		0.18
gMVP		0.34

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: rs904951966; hg19: chr3-125725367;