rs144200355

Variant names:

• chr2-43872296-A-T
• rs144200355
• NM_022437.3:c.1201A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-43872296-A-T
• chr2-43872296-A-G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_022437.3(ABCG8):​c.1201A>T​(p.Thr401Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,613,736 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. T401M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (15 hom.)
• Consequence: ABCG8 NM_022437.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 0.884
• Publications: 16 publications found

Genes affected

ABCG8 (HGNC:13887): (ATP binding cassette subfamily G member 8) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the White subfamily. The protein encoded by this gene functions to exclude non-cholesterol sterol entry at the intestinal level, promote excretion of cholesterol and sterols into bile, and to facilitate transport of sterols back into the intestinal lumen. It is expressed in a tissue-specific manner in the liver, intestine, and gallbladder. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG5. Mutations in this gene may contribute to sterol accumulation and atherosclerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]

ABCG8 Gene-Disease associations (from GenCC):

• sitosterolemia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, ClinGen, Orphanet
• sitosterolemia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_022437.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.015889764).
• BP6: Variant 2-43872296-A-T is Benign according to our data. Variant chr2-43872296-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198901.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022437.3. 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
	ABCG8	NM_022437.3	MANE Select	c.1201A>T	p.Thr401Ser	missense	Exon 8 of 13	NP_071882.1	Q9H221-1
	ABCG8	NM_001357321.2		c.1198A>T	p.Thr400Ser	missense	Exon 8 of 13	NP_001344250.1	Q9H221-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	ENST00000272286.4	TSL:1 MANE Select	c.1201A>T	p.Thr401Ser	missense	Exon 8 of 13	ENSP00000272286.2	Q9H221-1
	ABCG8	ENST00000881895.1		c.1201A>T	p.Thr401Ser	missense	Exon 8 of 13	ENSP00000551954.1
	ABCG8	ENST00000881900.1		c.1198A>T	p.Thr400Ser	missense	Exon 8 of 13	ENSP00000551959.1

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152104 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00152 AC: 380 AN: 250578 AF XY: 0.00138

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00234

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00210 AC: 3073 AN: 1461514 Hom.: 15 Cov.: 33 AF XY: 0.00208 AC XY: 1513 AN XY: 727038

African (AFR) AF: 0.000478 AC: 16 AN: 33472

American (AMR) AF: 0.00257 AC: 115 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000452 AC: 39 AN: 86236

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53188

Middle Eastern (MID) AF: 0.0132 AC: 76 AN: 5768

European-Non Finnish (NFE) AF: 0.00243 AC: 2702 AN: 1111940

Other (OTH) AF: 0.00184 AC: 111 AN: 60384

GnomAD4 genome AF: 0.00175 AC: 266 AN: 152222 Hom.: 1 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74410

African (AFR) AF: 0.000578 AC: 24 AN: 41538

American (AMR) AF: 0.00458 AC: 70 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00237 AC: 161 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00188 Hom.: 1

Bravo AF: 0.00199

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00144 AC: 175

EpiCase AF: 0.00360

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	not provided (6)
-	-	1	ABCG8-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Sitosterolemia 1 (1)
-	1	-	Sitosterolemia;C1969115:Gallbladder disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.88
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.083
Sift	Benign	0.057	T
Sift4G	Uncertain	0.018	D
Polyphen		0.63	P
Vest4		0.29
MVP		0.73
MPC		0.035
ClinPred		0.023	T
GERP RS		2.4
Varity_R		0.28
gMVP		0.44
Mutation Taster		=98/2	polymorphism

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: rs144200355; hg19: chr2-44099435; COSMIC: COSV99042252;