19-1054256-G-C

Variant names:

• chr19-1054256-G-C
• rs201060968
• NM_019112.4:c.3641G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_019112.4(ABCA7):​c.3641G>C​(p.Trp1214Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: ABCA7 NM_019112.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.81
• Publications: 9 publications found

Genes affected

ABCA7 (HGNC:37): (ATP binding cassette subfamily A member 7) The 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 intra-cellular 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. This full transporter has been detected predominantly in myelo-lymphatic tissues with the highest expression in peripheral leukocytes, thymus, spleen, and bone marrow. The function of this protein is not yet known; however, the expression pattern suggests a role in lipid homeostasis in cells of the immune system. [provided by RefSeq, Jul 2008]

ABCA7 Gene-Disease associations (from GenCC):

• Alzheimer disease 9

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA7	NM_019112.4	c.3641G>C	p.Trp1214Ser	missense_variant	Exon 27 of 47	ENST00000263094.11	NP_061985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA7	ENST00000263094.11	c.3641G>C	p.Trp1214Ser	missense_variant	Exon 27 of 47	5	NM_019112.4	ENSP00000263094.6
ABCA7	ENST00000433129.6	n.4321G>C		non_coding_transcript_exon_variant	Exon 26 of 44	1
ABCA7	ENST00000435683.7	n.1112G>C		non_coding_transcript_exon_variant	Exon 10 of 29	5		ENSP00000465322.2
ABCA7	ENST00000530092.2	n.98G>C		non_coding_transcript_exon_variant	Exon 2 of 5	4		ENSP00000437311.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;D;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.2	M;M;.
PhyloP100		5.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.0	D;D;.
REVEL	Pathogenic	0.71
Sift	Benign	0.20	T;T;.
Sift4G	Benign	0.30	T;T;T
Polyphen		0.41	B;B;D
Vest4		0.60
MutPred		0.67		Gain of disorder (P = 2e-04);Gain of disorder (P = 2e-04);.;
MVP		0.84
MPC		0.60
ClinPred		0.97	D
GERP RS		3.6
Varity_R		0.39
gMVP		0.68
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs201060968; hg19: chr19-1054255;