chr17-69250524-G-C

Variant names:

• chr17-69250524-G-C
• rs200779886
• NM_172232.4:c.4633C>G

Variant summary

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

The NM_172232.4(ABCA5):​c.4633C>G​(p.Arg1545Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,448,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R1545C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ABCA5 NM_172232.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.51
• Publications: 1 publications found

Genes affected

ABCA5 (HGNC:35): (ATP binding cassette subfamily A member 5) 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, but neither the substrate nor the function of this gene is known. Alternative splicing of this gene results in several transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

ABCA5 Gene-Disease associations (from GenCC):

• gingival fibromatosis-hypertrichosis syndrome

  Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Ambry Genetics
• ventricular tachycardia, familial

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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=0.1969305).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172232.4. 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
	ABCA5	NM_172232.4	MANE Select	c.4633C>G	p.Arg1545Gly	missense	Exon 36 of 39	NP_758424.1	Q8WWZ7-1
	ABCA5	NM_018672.5		c.4633C>G	p.Arg1545Gly	missense	Exon 35 of 38	NP_061142.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA5	ENST00000392676.8	TSL:1 MANE Select	c.4633C>G	p.Arg1545Gly	missense	Exon 36 of 39	ENSP00000376443.2	Q8WWZ7-1
	ABCA5	ENST00000588877.5	TSL:1	c.4633C>G	p.Arg1545Gly	missense	Exon 35 of 38	ENSP00000467882.1	Q8WWZ7-1
	ABCA5	ENST00000586995.5	TSL:1	n.*2279C>G		non_coding_transcript_exon	Exon 29 of 32	ENSP00000467251.1	Q6N017

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000839 AC: 2 AN: 238322 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1448998 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720620

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32676

American (AMR) AF: 0.00 AC: 0 AN: 41832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25760

East Asian (EAS) AF: 0.00 AC: 0 AN: 39062

South Asian (SAS) AF: 0.00 AC: 0 AN: 83568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1107414

Other (OTH) AF: 0.00 AC: 0 AN: 59828

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000233207), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.097
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.28
Sift	Benign	0.33	T
Sift4G	Benign	0.33	T
Polyphen		0.094	B
Vest4		0.44
MutPred		0.48		Loss of solvent accessibility (P = 0.1235)
MVP		0.84
MPC		0.072
ClinPred		0.22	T
GERP RS		6.1
Varity_R		0.076
gMVP		0.59
Mutation Taster		=94/6	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: rs200779886; hg19: chr17-67246665;