11-119150202-G-C

Variant names:

• chr11-119150202-G-C
• rs193920956
• NM_022169.5:c.237G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022169.5(ABCG4):​c.237G>C​(p.Arg79Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ABCG4 NM_022169.5 missense, splice_region
• Scores: Splicing: ADA: 0.002383
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25552016).

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.237G>C	p.Arg79Ser	missense splice_region	Exon 2 of 15	NP_071452.2
	ABCG4	NM_001142505.1		c.237G>C	p.Arg79Ser	missense splice_region	Exon 2 of 15	NP_001135977.1	Q9H172-1
	ABCG4	NM_001348191.2		c.237G>C	p.Arg79Ser	missense splice_region	Exon 2 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.237G>C	p.Arg79Ser	missense splice_region	Exon 2 of 15	ENSP00000481728.1	Q9H172-1
	ABCG4	ENST00000622721.1	TSL:1	c.237G>C	p.Arg79Ser	missense splice_region	Exon 1 of 14	ENSP00000484289.1	Q9H172-1
	ABCG4	ENST00000615496.4	TSL:2	c.237G>C	p.Arg79Ser	missense splice_region	Exon 2 of 15	ENSP00000479253.1	Q9H172-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 250064 AF XY: 0.0000148

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460924 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726614

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111416

Other (OTH) AF: 0.00 AC: 0 AN: 60342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.036
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.46	N
PhyloP100		3.0
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.19
Sift	Benign	0.11	T
Sift4G	Benign	0.19	T
Polyphen		0.65	P
Vest4		0.63
MutPred		0.48		Loss of MoRF binding (P = 0.0335)
MVP		0.62
ClinPred		0.51	D
GERP RS		2.4
PromoterAI		-0.00030	Neutral
Varity_R		0.24
gMVP		0.82
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0024
dbscSNV1_RF	Benign	0.10
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: rs193920956; hg19: chr11-119020912;