21-42219271-T-C

Position:

• chr21-42219271-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_016818.3(ABCG1):​c.9T>C​(p.Cys3=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,585,852 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (10 hom.)
• Consequence: ABCG1 NM_016818.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.57

Genes affected

ABCG1 (HGNC:73): (ATP binding cassette subfamily G member 1) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. 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). This protein is a member of the White subfamily. It is involved in macrophage cholesterol and phospholipids transport, and may regulate cellular lipid homeostasis in other cell types. Six alternative splice variants have been identified. [provided by RefSeq, Jul 2008]

LOC105372814 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 21-42219271-T-C is Benign according to our data. Variant chr21-42219271-T-C is described in ClinVar as [Benign]. Clinvar id is 3044620.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.57 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00499 (756/151544) while in subpopulation AFR AF= 0.0169 (693/40988). AF 95% confidence interval is 0.0159. There are 9 homozygotes in gnomad4. There are 361 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCG1	NM_016818.3	c.9T>C	p.Cys3=	synonymous_variant	1/15	ENST00000398449.8
LOC105372814	XR_937748.4	n.121+879A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG1	ENST00000398449.8	c.9T>C	p.Cys3=	synonymous_variant	1/15	1	NM_016818.3	P1

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 752 AN: 151432 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00135 AC: 286 AN: 212100 Hom.: 4 AF XY: 0.00109 AC XY: 127 AN XY: 116994

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.000444

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000143

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000289

Gnomad OTH exome AF: 0.000966

GnomAD4 exome AF: 0.000752 AC: 1079 AN: 1434308 Hom.: 10 Cov.: 32 AF XY: 0.000643 AC XY: 459 AN XY: 713332

Gnomad4 AFR exome AF: 0.0210

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.000315

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000155

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000176

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00499 AC: 756 AN: 151544 Hom.: 9 Cov.: 32 AF XY: 0.00487 AC XY: 361 AN XY: 74090

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00302 Hom.: 1

Bravo AF: 0.00618

Asia WGS AF: 0.00173 AC: 6 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ABCG1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs144415936; hg19: chr21-43639381;