11-119156981-C-A

Variant names:

• chr11-119156981-C-A
• rs12271907
• NM_022169.5:c.1035C>A

Variant summary

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

The NM_022169.5(ABCG4):​c.1035C>A​(p.Asn345Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N345N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ABCG4 NM_022169.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.901
• Publications: 7 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04336053).

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.1035C>A	p.Asn345Lys	missense	Exon 9 of 15	NP_071452.2
	ABCG4	NM_001142505.1		c.1035C>A	p.Asn345Lys	missense	Exon 9 of 15	NP_001135977.1	Q9H172-1
	ABCG4	NM_001348191.2		c.1035C>A	p.Asn345Lys	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.1035C>A	p.Asn345Lys	missense	Exon 9 of 15	ENSP00000481728.1	Q9H172-1
	ABCG4	ENST00000622721.1	TSL:1	c.1035C>A	p.Asn345Lys	missense	Exon 8 of 14	ENSP00000484289.1	Q9H172-1
	ABCG4	ENST00000533694.5	TSL:1	n.1948C>A		non_coding_transcript_exon	Exon 7 of 10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 249952 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460750 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726686

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111446

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0040
DANN	Benign	0.84
DEOGEN2	Benign	0.15	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.90
PrimateAI	Uncertain	0.51	T
Sift4G	Benign	0.81	T
Polyphen		0.072	B
Vest4		0.030
MutPred		0.45		Gain of ubiquitination at N345 (P = 0.0082)
MVP		0.32
ClinPred		0.082	T
GERP RS		-11
Varity_R		0.047
gMVP		0.36
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs12271907; hg19: chr11-119027691;