1-1512313-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001170535.3(ATAD3A):c.45C>T(p.Gly15=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,248,182 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (21 hom.)
• Consequence: ATAD3A NM_001170535.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.07

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-1512313-C-T is Benign according to our data. Variant chr1-1512313-C-T is described in ClinVar as [Benign]. Clinvar id is 709201.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-1512313-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00721 (1094/151750) while in subpopulation AFR AF= 0.0252 (1043/41372). AF 95% confidence interval is 0.0239. There are 14 homozygotes in gnomad4. There are 492 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATAD3A	NM_001170535.3	c.45C>T	p.Gly15=	synonymous_variant	1/16	ENST00000378756.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATAD3A	ENST00000378756.8	c.45C>T	p.Gly15=	synonymous_variant	1/16	1	NM_001170535.3	P1
ATAD3A	ENST00000378755.9	c.45C>T	p.Gly15=	synonymous_variant	1/16	2
ATAD3A	ENST00000672388.1	n.149C>T		non_coding_transcript_exon_variant	1/14

Frequencies

GnomAD3 genomes AF: 0.00717 AC: 1088 AN: 151646 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00817

GnomAD3 exomes AF: 0.00242 AC: 45 AN: 18578 Hom.: 0 AF XY: 0.00240 AC XY: 25 AN XY: 10396

Gnomad AFR exome AF: 0.0673

Gnomad AMR exome AF: 0.00519

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000748 AC: 820 AN: 1096432 Hom.: 21 Cov.: 30 AF XY: 0.000702 AC XY: 365 AN XY: 520058

Gnomad4 AFR exome AF: 0.0300

Gnomad4 AMR exome AF: 0.00213

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000325

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00721 AC: 1094 AN: 151750 Hom.: 14 Cov.: 32 AF XY: 0.00663 AC XY: 492 AN XY: 74176

Gnomad4 AFR AF: 0.0252

Gnomad4 AMR AF: 0.00210

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00808

Alfa AF: 0.00555 Hom.: 1

Bravo AF: 0.00844

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	15
Dann	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs541906634; hg19: chr1-1447693;