3-122795499-C-T

Variant names:

• chr3-122795499-C-T
• rs755722102
• NM_032839.3:c.307C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032839.3(SLC49A4):​c.307C>T​(p.Pro103Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000827 in 1,450,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: SLC49A4 NM_032839.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC49A4	NM_032839.3	c.307C>T	p.Pro103Ser	missense_variant	Exon 1 of 9	ENST00000261038.6	NP_116228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC49A4	ENST00000261038.6	c.307C>T	p.Pro103Ser	missense_variant	Exon 1 of 9	1	NM_032839.3	ENSP00000261038.5
SLC49A4	ENST00000477647.1	n.307C>T		non_coding_transcript_exon_variant	Exon 1 of 8	1		ENSP00000418554.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000827 AC: 12 AN: 1450390 Hom.: 0 Cov.: 34 AF XY: 0.0000111 AC XY: 8 AN XY: 721956

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000304

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.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.307C>T (p.P103S) alteration is located in exon 1 (coding exon 1) of the DIRC2 gene. This alteration results from a C to T substitution at nucleotide position 307, causing the proline (P) at amino acid position 103 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	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.85	T
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.35
Sift	Benign	0.063	T
Sift4G	Pathogenic	0.0	D
Vest4		0.73
MutPred		0.52		Loss of catalytic residue at P103 (P = 0.0343);
MVP		0.55
MPC		0.72
ClinPred		0.92	D
GERP RS		4.5
gMVP		0.87

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: rs755722102; hg19: chr3-122514346;