9-104903754-GC-GCC

Variant names:

• chr9-104903754-G-GC
• rs1799777
• NM_005502.4:c.-76dupG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005502.4(ABCA1):​c.-76dupG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,369,130 control chromosomes in the GnomAD database, including 12,187 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1169 hom., cov: 30)
  • Exomes 𝑓: 0.12 (11018 hom.)
• Consequence: ABCA1 NM_005502.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.30
• Publications: 17 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Tangier disease

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 9-104903754-G-GC is Benign according to our data. Variant chr9-104903754-G-GC is described in ClinVar as Benign. ClinVar VariationId is 364470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

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.-76dupG		5_prime_UTR	Exon 2 of 50	NP_005493.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.-76dupG		5_prime_UTR	Exon 2 of 50	ENSP00000363868.3	O95477
	ABCA1	ENST00000678995.1		c.-76dupG		5_prime_UTR	Exon 2 of 50	ENSP00000504612.1	A0A7I2V5U0
	ABCA1	ENST00000423487.6	TSL:2	c.-76dupG		5_prime_UTR	Exon 2 of 8	ENSP00000416623.2	B1AMI2

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16192 AN: 152098 Hom.: 1167 Cov.: 30

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.113

GnomAD4 exome AF: 0.125 AC: 152010 AN: 1216914 Hom.: 11018 Cov.: 17 AF XY: 0.129 AC XY: 78544 AN XY: 609266

African (AFR) AF: 0.0194 AC: 552 AN: 28520

American (AMR) AF: 0.191 AC: 6765 AN: 35472

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3532 AN: 24070

East Asian (EAS) AF: 0.196 AC: 6835 AN: 34886

South Asian (SAS) AF: 0.220 AC: 16574 AN: 75378

European-Finnish (FIN) AF: 0.104 AC: 4780 AN: 46114

Middle Eastern (MID) AF: 0.111 AC: 544 AN: 4908

European-Non Finnish (NFE) AF: 0.115 AC: 105405 AN: 915458

Other (OTH) AF: 0.135 AC: 7023 AN: 52108

GnomAD4 genome AF: 0.106 AC: 16206 AN: 152216 Hom.: 1169 Cov.: 30 AF XY: 0.109 AC XY: 8139 AN XY: 74398

African (AFR) AF: 0.0251 AC: 1043 AN: 41566

American (AMR) AF: 0.158 AC: 2415 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 500 AN: 3470

East Asian (EAS) AF: 0.180 AC: 927 AN: 5156

South Asian (SAS) AF: 0.243 AC: 1169 AN: 4820

European-Finnish (FIN) AF: 0.111 AC: 1176 AN: 10588

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8638 AN: 68014

Other (OTH) AF: 0.120 AC: 253 AN: 2112

Alfa AF: 0.113 Hom.: 144

Bravo AF: 0.106

Asia WGS AF: 0.217 AC: 751 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial High Density Lipoprotein Deficiency (1)
-	-	1	not provided (1)
-	-	1	Tangier disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=299/1	polymorphism (auto)

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: rs1799777; hg19: chr9-107666035; COSMIC: COSV66057838;