rs77542162

Variant names:

• chr17-69085137-A-G
• rs77542162
• NM_080284.3:c.4075T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3 BP4_Strong BS1 BS2

The NM_080284.3(ABCA6):​c.4075T>C​(p.Cys1359Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,612,520 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 32)
  • Exomes 𝑓: 0.017 (256 hom.)
• Consequence: ABCA6 NM_080284.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.69
• Publications: 65 publications found

Genes affected

ABCA6 (HGNC:36): (ATP binding cassette subfamily A member 6) The membrane-associated 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 intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White). This encoded protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This gene is clustered among 4 other ABC1 family members on 17q24 and may play a role in macrophage lipid homeostasis. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.02133444).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0101 (1539/152292) while in subpopulation NFE AF = 0.0183 (1245/68020). AF 95% confidence interval is 0.0175. There are 16 homozygotes in GnomAd4. There are 650 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080284.3. 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
	ABCA6	NM_080284.3	MANE Select	c.4075T>C	p.Cys1359Arg	missense	Exon 32 of 39	NP_525023.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA6	ENST00000284425.7	TSL:1 MANE Select	c.4075T>C	p.Cys1359Arg	missense	Exon 32 of 39	ENSP00000284425.1	Q8N139-1
	ABCA6	ENST00000886836.1		c.4216T>C	p.Cys1406Arg	missense	Exon 33 of 40	ENSP00000556895.1
	ABCA6	ENST00000886838.1		c.4171T>C	p.Cys1391Arg	missense	Exon 33 of 40	ENSP00000556897.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1539 AN: 152174 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00931 AC: 2282 AN: 245206 AF XY: 0.00951

Gnomad AFR exome AF: 0.00329

Gnomad AMR exome AF: 0.00294

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00517

Gnomad NFE exome AF: 0.0172

Gnomad OTH exome AF: 0.00949

GnomAD4 exome AF: 0.0169 AC: 24679 AN: 1460228 Hom.: 256 Cov.: 32 AF XY: 0.0163 AC XY: 11871 AN XY: 726342

African (AFR) AF: 0.00243 AC: 81 AN: 33400

American (AMR) AF: 0.00342 AC: 152 AN: 44382

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26086

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.00118 AC: 101 AN: 85930

European-Finnish (FIN) AF: 0.00644 AC: 344 AN: 53378

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.0208 AC: 23139 AN: 1111304

Other (OTH) AF: 0.0142 AC: 854 AN: 60330

GnomAD4 genome AF: 0.0101 AC: 1539 AN: 152292 Hom.: 16 Cov.: 32 AF XY: 0.00873 AC XY: 650 AN XY: 74458

African (AFR) AF: 0.00354 AC: 147 AN: 41566

American (AMR) AF: 0.00608 AC: 93 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0183 AC: 1245 AN: 68020

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.0150 Hom.: 60

Bravo AF: 0.0109

TwinsUK AF: 0.0191 AC: 71

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0200 AC: 172

ExAC AF: 0.00977 AC: 1186

EpiCase AF: 0.0170

EpiControl AF: 0.0151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.021	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.99
MPC		0.32
ClinPred		0.073	T
GERP RS		4.8
Varity_R		0.99
gMVP		0.76
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs77542162; hg19: chr17-67081278; COSMIC: COSV105823100;