rs200344678

Variant names:

• chr1-1534004-C-T
• rs200344678
• NM_001170535.3:c.1693C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS1

The NM_001170535.3(ATAD3A):​c.1693C>T​(p.His565Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000492 in 1,613,606 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: ATAD3A NM_001170535.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 5.66
• Publications: 2 publications found

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]

ATAD3A Gene-Disease associations (from GenCC):

• Harel-Yoon syndrome

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28841603).
• BP6: Variant 1-1534004-C-T is Benign according to our data. Variant chr1-1534004-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522903.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000295 (45/152298) while in subpopulation SAS AF = 0.000621 (3/4830). AF 95% confidence interval is 0.000368. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001170535.3. 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
	ATAD3A	NM_001170535.3	MANE Select	c.1693C>T	p.His565Tyr	missense	Exon 16 of 16	NP_001164006.1	Q9NVI7-2
	ATAD3A	NM_018188.5		c.1837C>T	p.His613Tyr	missense	Exon 16 of 16	NP_060658.3
	ATAD3A	NM_001170536.3		c.1456C>T	p.His486Tyr	missense	Exon 16 of 16	NP_001164007.1	Q9NVI7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATAD3A	ENST00000378756.8	TSL:1 MANE Select	c.1693C>T	p.His565Tyr	missense	Exon 16 of 16	ENSP00000368031.3	Q9NVI7-2
	ATAD3A	ENST00000378755.9	TSL:2	c.1837C>T	p.His613Tyr	missense	Exon 16 of 16	ENSP00000368030.5	Q9NVI7-1
	ATAD3A	ENST00000936382.1		c.1690C>T	p.His564Tyr	missense	Exon 16 of 16	ENSP00000606441.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000283 AC: 71 AN: 250764 AF XY: 0.000273

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000362

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000513 AC: 749 AN: 1461308 Hom.: 1 Cov.: 37 AF XY: 0.000499 AC XY: 363 AN XY: 727004

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86258

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53000

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5762

European-Non Finnish (NFE) AF: 0.000595 AC: 662 AN: 1111892

Other (OTH) AF: 0.000530 AC: 32 AN: 60386

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74480

African (AFR) AF: 0.0000722 AC: 3 AN: 41560

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.000276

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy (1)
-	1	-	Harel-Yoon syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.019
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.54
Sift	Benign	0.055	T
Sift4G	Uncertain	0.027	D
Polyphen		0.0020	B
Vest4		0.53
MVP		0.91
MPC		0.55
ClinPred		0.56	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.59
gMVP		0.86
Mutation Taster		=84/16	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: rs200344678; hg19: chr1-1469384;