17-68975977-C-T

Position:

• chr17-68975977-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080283.4(ABCA9):​c.4813G>A​(p.Asp1605Asn) variant causes a missense 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCA9 NM_080283.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

Genes affected

ABCA9 (HGNC:39): (ATP binding cassette subfamily A member 9) This gene is a member of the superfamily of ATP-binding cassette (ABC) transporters and the encoded protein contains two transmembrane domains and two nucleotide binding folds. 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 gene is a member of the ABC1 subfamily and is clustered with four other ABC1 family members on chromosome 17q24. Transcriptional expression of this gene is induced during monocyte differentiation into macrophages and is suppressed by cholesterol import. [provided by RefSeq, Jul 2008]

ABCA9-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07980353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA9	NM_080283.4	c.4813G>A	p.Asp1605Asn	missense_variant	39/39	ENST00000340001.9	NP_525022.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA9	ENST00000340001.9	c.4813G>A	p.Asp1605Asn	missense_variant	39/39	1	NM_080283.4	ENSP00000342216.3
ABCA9	ENST00000453985.6	c.4699G>A	p.Asp1567Asn	missense_variant	38/38	5		ENSP00000394264.2
ABCA9-AS1	ENST00000630625.1	n.377+31070C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Sep 02, 2024

The c.4813G>A (p.D1605N) alteration is located in exon 39 (coding exon 38) of the ABCA9 gene. This alteration results from a G to A substitution at nucleotide position 4813, causing the aspartic acid (D) at amino acid position 1605 to be replaced by an asparagine (N). 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	0.076
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	2.4
DANN	Benign	0.86
DEOGEN2	Benign	0.064	T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.35	T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.86	L;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.80	N;.
REVEL	Benign	0.10
Sift	Benign	0.70	T;.
Sift4G	Benign	0.50	T;T
Polyphen		0.0030	B;.
Vest4		0.088
MutPred		0.30		Loss of helix (P = 0.1299);.;
MVP		0.67
MPC		0.11
ClinPred		0.038	T
GERP RS		2.8
Varity_R		0.039
gMVP		0.11

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: rs199809476; hg19: chr17-66972118;