19-1046521-T-G

Variant names:

• chr19-1046521-T-G
• rs3764650
• NM_019112.4:c.1622+115T>G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_019112.4(ABCA7):c.1622+115T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.109 (AC=150,016) in the gnomAD database across 1,381,032 control chromosomes, including 11,058 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.361. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (2175 hom., cov: 33)
  • Exomes 𝑓: 0.10 (8883 hom.)
• Consequence: ABCA7 NM_019112.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.893
• Publications: 228 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)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3609 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_019112.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ABCA7 NM_019112.4	MANE Select	c.1622+115T>G	intron	Intron 13 of 46	Prot: NP_061985.2 UniProt:

ABCA7 NM_019112.4

MANE Select

HGVSc / HGVSpc.1622+115T>G

Exon rankIntron 13 of 46

intron

Prot: NP_061985.2UniProt: Q8IZY2-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ABCA7 ENST00000263094.11	TSL:5MANE Select	c.1622+115T>G	intron	Intron 13 of 46	Prot: ENSP00000263094.6 UniProt:
	ABCA7 ENST00000433129.6	TSL:1	n.2302+115T>G	intron	Intron 12 of 43	Prot:
	ABCA7 ENST00000533574.1	TSL:4	n.263+117T>G	intron	Intron 2 of 3	Prot:

ABCA7 ENST00000263094.11

TSL:5MANE Select

HGVSc / HGVSpc.1622+115T>G

Exon rankIntron 13 of 46

intron

Prot: ENSP00000263094.6UniProt: Q8IZY2-1

ABCA7 ENST00000433129.6

TSL:1

HGVSc / HGVSpn.2302+115T>G

Exon rankIntron 12 of 43

intron

Prot:

ABCA7 ENST00000533574.1

TSL:4

HGVSc / HGVSpn.263+117T>G

Exon rankIntron 2 of 3

intron

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.145	AC:22044	Hom:2154	AN:151930	Cov:33
GnomAD4 exome	AF: 0.104	AC:127913	Hom:8883	AN:1228986	Cov:
GnomAD4 genome	AF: 0.145	AC:22103	Hom:2175	AN:152046	Cov:33
TOPMed (Bravo)	AF: 0.154	AC:40797	Hom:3974	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.113	AC:76929	Hom:5623	AN:679152	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.139	AC:326	Hom:35	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.301	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0967	AC:29	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.242	AC:841	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.330	AC:2381	Hom:	AN:7214	Cov:
Qatari Genome	AF: 0.159	AC:28	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.402	AC:48071	Hom:9621	AN:119706	Cov:
Turkish Variome	AF: 0.114	AC:176	Hom:9	AN:1546	Cov:
UK10K	AF: 0.0895	AC:677	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.302	AC:2709	Hom:438	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.101	6603	65680	0.0909	10857	119376

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.2
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.89
DANN	Benign	0.53
GPN-Star LLR	N/A	0.90
GPN-Star score	N/A	-0.90
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-0.89
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3764650;

hg19: chr19-1046520;

COSMIC: COSV54028967;

COSMIC: COSV54028967;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar