17-68875318-C-A

Variant names:

• chr17-68875318-C-A
• rs765746708
• NM_001288985.2:c.4573G>T

Variant summary

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

The NM_001288985.2(ABCA8):​c.4573G>T​(p.Val1525Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1525M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCA8 NM_001288985.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.745
• Publications: 0 publications found

Genes affected

ABCA8 (HGNC:38): (ATP binding cassette subfamily A member 8) 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, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. The encoded protein may regulate lipid metabolism and be involved in the formation and maintenance of myelin. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

LOC105371874 (HGNC:):

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=0.077640295).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001288985.2. 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
	ABCA8	NM_001288985.2	MANE Select	c.4573G>T	p.Val1525Leu	missense	Exon 37 of 40	NP_001275914.1	O94911-3
	ABCA8	NM_001288986.2		c.4558G>T	p.Val1520Leu	missense	Exon 36 of 39	NP_001275915.1	A0A0A0MSU4
	ABCA8	NM_007168.4		c.4453G>T	p.Val1485Leu	missense	Exon 35 of 38	NP_009099.1	O94911-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA8	ENST00000586539.6	TSL:1 MANE Select	c.4573G>T	p.Val1525Leu	missense	Exon 37 of 40	ENSP00000467271.1	O94911-3
	ABCA8	ENST00000430352.6	TSL:1	c.4558G>T	p.Val1520Leu	missense	Exon 36 of 39	ENSP00000402814.3	A0A0A0MSU4
	ABCA8	ENST00000269080.6	TSL:1	c.4453G>T	p.Val1485Leu	missense	Exon 35 of 38	ENSP00000269080.1	O94911-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.9
DANN	Benign	0.96
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.74
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.10
Sift	Benign	0.046	D
Sift4G	Benign	0.17	T
Polyphen		0.031	B
Vest4		0.14
MutPred		0.32		Gain of helix (P = 0.062)
MVP		0.56
MPC		0.057
ClinPred		0.074	T
GERP RS		-0.98
Varity_R		0.12
gMVP		0.23

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: rs765746708; hg19: chr17-66871459;