chr11-119156946-G-A

Variant names:

• chr11-119156946-G-A
• rs201193587
• NM_022169.5:c.1000G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_022169.5(ABCG4):​c.1000G>A​(p.Ala334Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ABCG4 NM_022169.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.387
• Publications: 3 publications found

Genes affected

ABCG4 (HGNC:13884): (ATP binding cassette subfamily G member 4) The protein encoded by this gene is a member of the ATP-binding cassette (ABC) transporter superfamily. 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). The encoded protein is a member of the White subfamily and plays an important role in cellular cholesterol homeostasis. This protein functions as either a homodimer or as a heterodimer with another ABC subfamily protein such as ABCG1. [provided by RefSeq, Jan 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036245823).
• BP6: Variant 11-119156946-G-A is Benign according to our data. Variant chr11-119156946-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2385157.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022169.5. 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
	ABCG4	NM_022169.5	MANE Select	c.1000G>A	p.Ala334Thr	missense	Exon 9 of 15	NP_071452.2
	ABCG4	NM_001142505.1		c.1000G>A	p.Ala334Thr	missense	Exon 9 of 15	NP_001135977.1	Q9H172-1
	ABCG4	NM_001348191.2		c.1000G>A	p.Ala334Thr	missense	Exon 9 of 15	NP_001335120.1	Q9H172-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG4	ENST00000619701.5	TSL:1 MANE Select	c.1000G>A	p.Ala334Thr	missense	Exon 9 of 15	ENSP00000481728.1	Q9H172-1
	ABCG4	ENST00000622721.1	TSL:1	c.1000G>A	p.Ala334Thr	missense	Exon 8 of 14	ENSP00000484289.1	Q9H172-1
	ABCG4	ENST00000533694.5	TSL:1	n.1913G>A		non_coding_transcript_exon	Exon 7 of 10

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251034 AF XY: 0.0000295

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727174

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000112 AC: 5 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111948

Other (OTH) AF: 0.0000331 AC: 2 AN: 60380

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.0000483 AC: 2 AN: 41432

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.5
DANN	Benign	0.86
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.30	N
PhyloP100		0.39
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.0080
MutPred		0.28		Loss of sheet (P = 0.0315)
MVP		0.39
ClinPred		0.021	T
GERP RS		-2.3
Varity_R		0.030
gMVP		0.42
Mutation Taster		=93/7	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: rs201193587; hg19: chr11-119027656; COSMIC: COSV56643434; COSMIC: COSV56643434;