NM_003049.4:c.800C>T

Variant names:

• chr14-69778476-G-A
• rs2296651
• NM_003049.4:c.800C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003049.4(SLC10A1):​c.800C>T​(p.Ser267Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00173 in 1,613,510 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (18 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (148 hom.)
• Consequence: SLC10A1 NM_003049.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:3
• Conservation: PhyloP100: 5.56
• Publications: 128 publications found

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]

SLC10A1 Gene-Disease associations (from GenCC):

• hypercholanemia, familial, 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052731335).
• BP6: Variant 14-69778476-G-A is Benign according to our data. Variant chr14-69778476-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 501461.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0642 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003049.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC10A1	NM_003049.4	MANE Select	c.800C>T	p.Ser267Phe	missense	Exon 4 of 5	NP_003040.1	Q14973

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC10A1	ENST00000216540.5	TSL:1 MANE Select	c.800C>T	p.Ser267Phe	missense	Exon 4 of 5	ENSP00000216540.4	Q14973
	SLC10A1	ENST00000871518.1		c.851C>T	p.Ser284Phe	missense	Exon 4 of 5	ENSP00000541577.1
	SLC10A1	ENST00000871519.1		c.836C>T	p.Ser279Phe	missense	Exon 5 of 6	ENSP00000541578.1

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 152184 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0708

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00629 AC: 1579 AN: 250862 AF XY: 0.00558

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0830

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00160 AC: 2340 AN: 1461208 Hom.: 148 Cov.: 31 AF XY: 0.00141 AC XY: 1027 AN XY: 726962

African (AFR) AF: 0.000568 AC: 19 AN: 33438

American (AMR) AF: 0.000314 AC: 14 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0427 AC: 1696 AN: 39684

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5582

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111770

Other (OTH) AF: 0.00983 AC: 593 AN: 60352

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152302 Hom.: 18 Cov.: 31 AF XY: 0.00299 AC XY: 223 AN XY: 74462

African (AFR) AF: 0.00142 AC: 59 AN: 41568

American (AMR) AF: 0.00111 AC: 17 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0702 AC: 363 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00209 Hom.: 89

Bravo AF: 0.00363

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00568 AC: 689

Asia WGS AF: 0.0230 AC: 78 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Hypercholanemia, familial, 2 (2)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	-	Hepatitis B virus, resistance to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.6
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.012	D
Polyphen		0.96	D
Vest4		0.52
MVP		0.79
MPC		0.0023
ClinPred		0.034	T
GERP RS		4.8
Varity_R		0.16
gMVP		0.80
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2296651; hg19: chr14-70245193;