chr1-1512287-A-G

Position:

• chr1-1512287-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001170535.3(ATAD3A):​c.19A>G​(p.Ile7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 151,686 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I7L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (140 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATAD3A NM_001170535.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.859

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049882233).
• BP6: Variant 1-1512287-A-G is Benign according to our data. Variant chr1-1512287-A-G is described in ClinVar as [Benign]. Clinvar id is 1675332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0102 (1552/151686) while in subpopulation AMR AF= 0.0132 (201/15258). AF 95% confidence interval is 0.0123. There are 13 homozygotes in gnomad4. There are 730 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATAD3A	NM_001170535.3	c.19A>G	p.Ile7Val	missense_variant	1/16	ENST00000378756.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATAD3A	ENST00000378756.8	c.19A>G	p.Ile7Val	missense_variant	1/16	1	NM_001170535.3	P1
ATAD3A	ENST00000378755.9	c.19A>G	p.Ile7Val	missense_variant	1/16	2
ATAD3A	ENST00000672388.1	n.123A>G		non_coding_transcript_exon_variant	1/14

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1551 AN: 151586 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00751

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000981

Gnomad SAS AF: 0.0123

Gnomad FIN AF: 0.00521

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00961

GnomAD3 exomes AF: 0.00329 AC: 184 AN: 55982 Hom.: 1 AF XY: 0.00299 AC XY: 94 AN XY: 31408

Gnomad AFR exome AF: 0.00418

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.00135

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00536

Gnomad FIN exome AF: 0.00289

Gnomad NFE exome AF: 0.00371

Gnomad OTH exome AF: 0.00243

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00418 AC: 4596 AN: 1100304 Hom.: 140 Cov.: 30 AF XY: 0.00422 AC XY: 2213 AN XY: 524940

Gnomad4 AFR exome AF: 0.00302

Gnomad4 AMR exome AF: 0.00483

Gnomad4 ASJ exome AF: 0.00419

Gnomad4 EAS exome AF: 0.0000715

Gnomad4 SAS exome AF: 0.00415

Gnomad4 FIN exome AF: 0.00615

Gnomad4 NFE exome AF: 0.00420

Gnomad4 OTH exome AF: 0.00533

GnomAD4 genome AF: 0.0102 AC: 1552 AN: 151686 Hom.: 13 Cov.: 32 AF XY: 0.00985 AC XY: 730 AN XY: 74140

Gnomad4 AFR AF: 0.00749

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000984

Gnomad4 SAS AF: 0.0127

Gnomad4 FIN AF: 0.00521

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.00951

Alfa AF: 0.00434 Hom.: 0

Bravo AF: 0.0104

ExAC AF: 0.00242 AC: 247

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Harel-Yoon syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

African/African American population allele frequency is 1.231% (rs201315462, 884/67870 alleles, 8 homozygotes in gnomAD v3.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

ATAD3A: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.51
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.74	N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.28
Sift	Benign	0.55	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.0	.;B
Vest4		0.11
MVP		0.44
MPC		0.28
ClinPred		0.00089	T
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.040
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs201314162; hg19: chr1-1447667;