14-69776375-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_003049.4(SLC10A1):c.957G>A(p.Met319Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,314 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M319T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SLC10A1 NM_003049.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.24

Genes affected

SLC10A1 (HGNC:10905): (solute carrier family 10 member 1) The protein encoded by this gene belongs to the sodium/bile acid cotransporter family, which are integral membrane glycoproteins that participate in the enterohepatic circulation of bile acids. Two homologous transporters are involved in the reabsorption of bile acids; the ileal sodium/bile acid cotransporter with an apical cell localization that absorbs bile acids from the intestinal lumen, bile duct and kidney, and the liver-specific sodium/bile acid cotransporter, represented by this protein, that is found in the basolateral membranes of hepatocytes. Bile acids are the catabolic product of cholesterol metabolism, hence this protein is important for cholesterol homeostasis. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035327077).
• BP6: Variant 14-69776375-C-T is Benign according to our data. Variant chr14-69776375-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 500558.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC10A1	NM_003049.4	c.957G>A	p.Met319Ile	missense_variant	5/5	ENST00000216540.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC10A1	ENST00000216540.5	c.957G>A	p.Met319Ile	missense_variant	5/5	1	NM_003049.4	P1

Frequencies

GnomAD3 genomes AF: 0.000587 AC: 89 AN: 151622 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000184 AC: 46 AN: 250654 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135548

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000108 AC: 158 AN: 1461576 Hom.: 0 Cov.: 30 AF XY: 0.000103 AC XY: 75 AN XY: 727086

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000666

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000600 AC: 91 AN: 151738 Hom.: 0 Cov.: 32 AF XY: 0.000634 AC XY: 47 AN XY: 74182

Gnomad4 AFR AF: 0.00199

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000609 Hom.: 0

Bravo AF: 0.000574

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 23, 2017

- -

SLC10A1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	0.10
Dann	Benign	0.65
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.30	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.40		Gain of sheet (P = 4e-04);
MVP		0.14
MPC		0.0014
ClinPred		0.0030	T
GERP RS		0.96
Varity_R		0.065
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs149272163; hg19: chr14-70243092;