chr17-68869777-T-G

Position:

• chr17-68869777-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000586539.6(ABCA8):​c.4634A>C​(p.Tyr1545Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCA8 ENST00000586539.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.171

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27899206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA8	NM_001288985.2	c.4634A>C	p.Tyr1545Ser	missense_variant, splice_region_variant	38/40	ENST00000586539.6	NP_001275914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA8	ENST00000586539.6	c.4634A>C	p.Tyr1545Ser	missense_variant, splice_region_variant	38/40	1	NM_001288985.2	ENSP00000467271.1
ABCA8	ENST00000430352.6	c.4619A>C	p.Tyr1540Ser	missense_variant, splice_region_variant	37/39	1		ENSP00000402814.3
ABCA8	ENST00000269080.6	c.4514A>C	p.Tyr1505Ser	missense_variant, splice_region_variant	36/38	1		ENSP00000269080.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2024

The c.4514A>C (p.Y1505S) alteration is located in exon 36 (coding exon 35) of the ABCA8 gene. This alteration results from a A to C substitution at nucleotide position 4514, causing the tyrosine (Y) at amino acid position 1505 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.24	T;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.38	T;T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.1	M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-7.0	D;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.10	T;.;.
Sift4G	Uncertain	0.012	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.38
MutPred		0.42		Gain of disorder (P = 0.0064);.;.;
MVP		0.54
MPC		0.38
ClinPred		0.71	D
GERP RS		-5.5
Varity_R		0.27
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-66865918;