rs193920956

chr11-119150202-G-Cchr11-119150202-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 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. 13/22 in silico tools predict a benign outcome for this variant. 2/2 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 same amino acid change has been previously reported as Uncertain significancein 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

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ABCG4
• BP4: Computational evidence support a benign effect (MetaRNN=0.25552016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCG4	NM_022169.5	c.237G>C	p.Arg79Ser	missense_variant, splice_region_variant	2/15	ENST00000619701.5
ABCG4	NM_001142505.1	c.237G>C	p.Arg79Ser	missense_variant, splice_region_variant	2/15
ABCG4	NM_001348191.2	c.237G>C	p.Arg79Ser	missense_variant, splice_region_variant	2/15
ABCG4	NM_001348192.2	c.-2G>C		splice_region_variant, 5_prime_UTR_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG4	ENST00000619701.5	c.237G>C	p.Arg79Ser	missense_variant, splice_region_variant	2/15	1	NM_022169.5	P1
ABCG4	ENST00000622721.1	c.237G>C	p.Arg79Ser	missense_variant, splice_region_variant	1/14	1		P1
ABCG4	ENST00000615496.4	c.237G>C	p.Arg79Ser	missense_variant, splice_region_variant	2/15	2		P1
ABCG4	ENST00000524604.5	c.237G>C	p.Arg79Ser	missense_variant, splice_region_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250064 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135272

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

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 v4.3

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;.;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.036
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.46	N;.;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.65	P;.;P;P
Vest4		0.63
MutPred		0.48		Loss of MoRF binding (P = 0.0335);Loss of MoRF binding (P = 0.0335);Loss of MoRF binding (P = 0.0335);Loss of MoRF binding (P = 0.0335);
MVP		0.62
ClinPred		0.51	D
GERP RS		2.4
Varity_R		0.24
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs193920956; hg19: chr11-119020912;