NM_022169.5:c.1035C>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022169.5(ABCG4):​c.1035C>G​(p.Asn345Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,612,868 control chromosomes in the GnomAD database, including 2,373 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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: 𝑓 0.068 (1164 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (1209 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038556159).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.0679 AC: 10315 AN: 152000 Hom.: 1158 Cov.: 32

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.0489

GnomAD2 exomes AF: 0.0181 AC: 4532 AN: 249952 AF XY: 0.0133

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000478

Gnomad OTH exome AF: 0.00822

GnomAD4 exome AF: 0.00740 AC: 10812 AN: 1460750 Hom.: 1209 Cov.: 31 AF XY: 0.00640 AC XY: 4654 AN XY: 726688

African (AFR) AF: 0.257 AC: 8610 AN: 33456

American (AMR) AF: 0.0147 AC: 655 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26010

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.000650 AC: 56 AN: 86100

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5760

European-Non Finnish (NFE) AF: 0.000304 AC: 338 AN: 1111446

Other (OTH) AF: 0.0175 AC: 1053 AN: 60326

GnomAD4 genome AF: 0.0681 AC: 10352 AN: 152118 Hom.: 1164 Cov.: 32 AF XY: 0.0656 AC XY: 4878 AN XY: 74386

African (AFR) AF: 0.235 AC: 9735 AN: 41416

American (AMR) AF: 0.0284 AC: 434 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68012

Other (OTH) AF: 0.0483 AC: 102 AN: 2110

Alfa AF: 0.00410 Hom.: 37

Bravo AF: 0.0831

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.222 AC: 977

ESP6500EA AF: 0.000815 AC: 7

ExAC AF: 0.0221 AC: 2682

EpiCase AF: 0.000873

EpiControl AF: 0.000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0040
DANN	Benign	0.83
DEOGEN2	Benign	0.15	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	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)
ClinPred		0.0081	T
GERP RS		-11
Varity_R		0.047
gMVP		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;