chr1-1512436-G-A

Position:

• chr1-1512436-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001170535.3(ATAD3A):​c.168G>A​(p.Glu56=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00801 in 149,064 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (11 hom., cov: 29)
  • Exomes 𝑓: 0.0079 (10 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATAD3A NM_001170535.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.71

Genes affected

ATAD3A (HGNC:25567): (ATPase family AAA domain containing 3A) This gene encodes a ubiquitously expressed mitochondrial membrane protein that contributes to mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. This gene is a member of the ATPase family AAA-domain containing 3 gene family which, in humans, includes two other paralogs. Naturally occurring mutations in this gene are associated with distinct neurological syndromes including Harel-Yoon syndrome. High-level expression of this gene is associated with poor survival in breast cancer patients. A homozygous knockout of the orthologous gene in mice results in embryonic lethality at day 7.5 due to growth retardation and defective development of the trophoblast lineage. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-1512436-G-A is Benign according to our data. Variant chr1-1512436-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 770482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.71 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00801 (1194/149064) while in subpopulation AMR AF= 0.0282 (424/15028). AF 95% confidence interval is 0.026. There are 11 homozygotes in gnomad4. There are 584 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATAD3A	NM_001170535.3	c.168G>A	p.Glu56=	synonymous_variant	1/16	ENST00000378756.8	NP_001164006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATAD3A	ENST00000378756.8	c.168G>A	p.Glu56=	synonymous_variant	1/16	1	NM_001170535.3	ENSP00000368031	P1
ATAD3A	ENST00000378755.9	c.168G>A	p.Glu56=	synonymous_variant	1/16	2		ENSP00000368030
ATAD3A	ENST00000672388.1	n.272G>A		non_coding_transcript_exon_variant	1/14
ATAD3A	ENST00000339113.9	c.54G>A	p.Glu18=	synonymous_variant, NMD_transcript_variant	1/17	2		ENSP00000339421

Frequencies

GnomAD3 genomes AF: 0.00801 AC: 1194 AN: 148978 Hom.: 11 Cov.: 29

Gnomad AFR AF: 0.00199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.00696

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.00252

Gnomad FIN AF: 0.00993

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00718

Gnomad OTH AF: 0.00685

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00793 AC: 8500 AN: 1071846 Hom.: 10 Cov.: 31 AF XY: 0.00803 AC XY: 4075 AN XY: 507588

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.0402

Gnomad4 ASJ exome AF: 0.00599

Gnomad4 EAS exome AF: 0.0167

Gnomad4 SAS exome AF: 0.00256

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.00761

Gnomad4 OTH exome AF: 0.00915

GnomAD4 genome AF: 0.00801 AC: 1194 AN: 149064 Hom.: 11 Cov.: 29 AF XY: 0.00802 AC XY: 584 AN XY: 72820

Gnomad4 AFR AF: 0.00201

Gnomad4 AMR AF: 0.0282

Gnomad4 ASJ AF: 0.00696

Gnomad4 EAS AF: 0.0112

Gnomad4 SAS AF: 0.00252

Gnomad4 FIN AF: 0.00993

Gnomad4 NFE AF: 0.00719

Gnomad4 OTH AF: 0.00678

Alfa AF: 0.00943 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Uncertain	0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs564012773; hg19: chr1-1447816;