rs1054911177

Variant names:

• chr17-68877537-G-A
• rs1054911177
• NM_001288985.2:c.4181C>T

Variant summary

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

The NM_001288985.2(ABCA8):​c.4181C>T​(p.Ala1394Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ABCA8 NM_001288985.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.4181C>T	p.Ala1394Val	missense	Exon 33 of 40	NP_001275914.1	O94911-3
	ABCA8	NM_001288986.2		c.4166C>T	p.Ala1389Val	missense	Exon 32 of 39	NP_001275915.1	A0A0A0MSU4
	ABCA8	NM_007168.4		c.4061C>T	p.Ala1354Val	missense	Exon 31 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.4181C>T	p.Ala1394Val	missense	Exon 33 of 40	ENSP00000467271.1	O94911-3
	ABCA8	ENST00000430352.6	TSL:1	c.4166C>T	p.Ala1389Val	missense	Exon 32 of 39	ENSP00000402814.3	A0A0A0MSU4
	ABCA8	ENST00000269080.6	TSL:1	c.4061C>T	p.Ala1354Val	missense	Exon 31 of 38	ENSP00000269080.1	O94911-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461500 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727028

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111774

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000611 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0052	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.085	D
MutationAssessor	Benign	0.36	N
PhyloP100		1.5
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.33
Sift	Benign	0.27	T
Sift4G	Benign	0.55	T
Polyphen		0.69	P
Vest4		0.080
MutPred		0.66		Loss of disorder (P = 0.1129)
MVP		0.83
MPC		0.26
ClinPred		0.71	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.56
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: -18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1054911177; hg19: chr17-66873678;