9-104928121-G-C

Variant names:

• chr9-104928121-G-C
• rs111292742
• NM_005502.4:c.-279C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005502.4(ABCA1):​c.-279C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 152,348 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (65 hom., cov: 33)
  • Exomes 𝑓: 0.019 (0 hom.)
• Consequence: ABCA1 NM_005502.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -3.99
• Publications: 8 publications found

Genes affected

ABCA1 (HGNC:29): (ATP binding cassette subfamily A member 1) 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. With cholesterol as its substrate, this protein functions as a cholesteral efflux pump in the cellular lipid removal pathway. Mutations in both alleles of this gene cause Tangier disease and familial high-density lipoprotein (HDL) deficiency. [provided by RefSeq, Sep 2019]

ABCA1 Gene-Disease associations (from GenCC):

• hypoalphalipoproteinemia, primary, 1

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Tangier disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• apolipoprotein A-I deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000226334 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 9-104928121-G-C is Benign according to our data. Variant chr9-104928121-G-C is described in ClinVar as Benign. ClinVar VariationId is 364479.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0223 (3394/152242) while in subpopulation NFE AF = 0.0347 (2357/68018). AF 95% confidence interval is 0.0335. There are 65 homozygotes in GnomAd4. There are 1682 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 65 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005502.4. 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
	ABCA1	NM_005502.4	MANE Select	c.-279C>G		5_prime_UTR	Exon 1 of 50	NP_005493.2
	LOC105376196	NR_188620.1		n.1122+211G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.-279C>G		5_prime_UTR	Exon 1 of 50	ENSP00000363868.3
	ABCA1	ENST00000678995.1		c.-279C>G		5_prime_UTR	Exon 1 of 50	ENSP00000504612.1
	ABCA1	ENST00000423487.6	TSL:2	c.-279C>G		5_prime_UTR	Exon 1 of 8	ENSP00000416623.2

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3395 AN: 152126 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.00596

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00995

Gnomad FIN AF: 0.0471

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.0189 AC: 2 AN: 106 Hom.: 0 Cov.: 0 AF XY: 0.0233 AC XY: 2 AN XY: 86

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 6

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0227 AC: 2 AN: 88

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.0223 AC: 3394 AN: 152242 Hom.: 65 Cov.: 33 AF XY: 0.0226 AC XY: 1682 AN XY: 74432

African (AFR) AF: 0.00594 AC: 247 AN: 41554

American (AMR) AF: 0.0111 AC: 169 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00996 AC: 48 AN: 4820

European-Finnish (FIN) AF: 0.0471 AC: 500 AN: 10606

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0347 AC: 2357 AN: 68018

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0259 Hom.: 45

Bravo AF: 0.0191

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hypoalphalipoproteinemia, primary, 1 (1)
-	-	1	Tangier disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.5
DANN	Benign	0.65
PhyloP100		-4.0
PromoterAI		0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=297/3	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: rs111292742; hg19: chr9-107690402;