Genetic Variant SLC49A4:p.Thr171Lys (chr3-122826874-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032839.3(SLC49A4):c.512C>A(p.Thr171Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T171M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC49A4
NM_032839.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.53

Variant links:

Genes affected

SLC49A4 (HGNC:16628): (solute carrier family 49 member 4) This gene encodes a membrane-bound protein from the major facilitator superfamily of transporters. Disruption of this gene by translocation has been associated with haplo-insufficiency and renal cell carcinomas. Alternatively spliced transcript variants have been described, but their biological validity has not yet been determined. [provided by RefSeq, Jul 2008]

SLC49A4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC49A4	NM_032839.3 link	c.512C>A	p.Thr171Lys	missense_variant	Exon 3 of 9	ENST00000261038.6	NP_116228.1	Q96SL1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC49A4	ENST00000261038.6 link	c.512C>A	p.Thr171Lys	missense_variant	Exon 3 of 9	1	NM_032839.3	ENSP00000261038.5	Q96SL1-1
SLC49A4	ENST00000477647.1 link	n.*70C>A		non_coding_transcript_exon_variant	Exon 2 of 8	1		ENSP00000418554.1	Q05BS2
SLC49A4	ENST00000477647.1 link	n.*70C>A		3_prime_UTR_variant	Exon 2 of 8	1		ENSP00000418554.1	Q05BS2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251302

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727214

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.512C>A (p.T171K) alteration is located in exon 3 (coding exon 3) of the DIRC2 gene. This alteration results from a C to A substitution at nucleotide position 512, causing the threonine (T) at amino acid position 171 to be replaced by a lysine (K). 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

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

0.98

Eigen

Benign

0.015

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.86

M_CAP

Benign

0.028

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.82

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.31

Sift

Uncertain

0.010

Sift4G

Uncertain

0.027

Vest4

0.93

MutPred

0.68

Gain of ubiquitination at T171 (P = 0.0219);

MVP

0.32

MPC

0.39

ClinPred

0.87

GERP RS

5.0

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over