4-682272-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_032219.4(SLC49A3):c.1366C>T(p.Pro456Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000819 in 1,220,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: SLC49A3 NM_032219.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.367

Genes affected

SLC49A3 (HGNC:26177): (solute carrier family 49 member 3) Predicted to enable transmembrane transporter activity. Predicted to be involved in transmembrane transport. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039709657).
• BP6: Variant 4-682272-G-A is Benign according to our data. Variant chr4-682272-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3164970.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC49A3	NM_032219.4	c.1366C>T	p.Pro456Ser	missense_variant	10/10	ENST00000322224.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC49A3	ENST00000322224.9	c.1366C>T	p.Pro456Ser	missense_variant	10/10	1	NM_032219.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000920 AC: 1 AN: 108734 Hom.: 0 AF XY: 0.0000164 AC XY: 1 AN XY: 60838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000134

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.19e-7 AC: 1 AN: 1220372 Hom.: 0 Cov.: 31 AF XY: 0.00000169 AC XY: 1 AN XY: 592904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000323

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000854 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	0.65
Dann	Benign	0.75
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0098	N
LIST_S2	Benign	0.44	T;T;T;T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.040	T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.020	N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.34	T;T;T;T
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.010	B;B;B;B
Vest4		0.082
MutPred		0.25		.;.;Loss of catalytic residue at P456 (P = 0.0227);.;
MVP		0.32
MPC		0.074
ClinPred		0.064	T
GERP RS		-4.9
Varity_R		0.021
gMVP		0.24

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: rs774562463; hg19: chr4-676061;