15-65050075-T-C

Position:

• chr15-65050075-T-C

Variant summary

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

The NM_178859.4(SLC51B):​c.71T>C​(p.Met24Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,318 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC51B NM_178859.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

Genes affected

SLC51B (HGNC:29956): (SLC51 subunit beta) Predicted to enable protein heterodimerization activity and transmembrane transporter activity. Involved in bile acid secretion. Located in basolateral plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

RASL12 (HGNC:30289): (RAS like family 12) Predicted to enable GDP binding activity; GTP binding activity; and GTPase activity. Predicted to be involved in signal transduction. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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/exons	MANE	Protein	UniProt
SLC51B	NM_178859.4	c.71T>C	p.Met24Thr	missense_variant	2/4	ENST00000334287.3	NP_849190.2
SLC51B	XM_005254159.6	c.71T>C	p.Met24Thr	missense_variant	2/4		XP_005254216.1
RASL12	XM_017022296.2	c.*1915A>G		3_prime_UTR_variant	5/5		XP_016877785.1
RASL12	XM_005254434.5	c.426-4331A>G		intron_variant			XP_005254491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC51B	ENST00000334287.3	c.71T>C	p.Met24Thr	missense_variant	2/4	2	NM_178859.4	ENSP00000335292.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399318 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

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

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2023

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 24 of the SLC51B protein (p.Met24Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC51B-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0097	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	2.0	M
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.47		Gain of sheet (P = 0.039);
MVP		0.34
MPC		0.35
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.54
gMVP		0.36

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: rs1483414364; hg19: chr15-65342413;