chr1-1485777-G-A

Variant names:

• chr1-1485777-G-A
• rs1622213
• NM_031921.6:c.907-5G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_031921.6(ATAD3B):​c.907-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00835 in 1,610,472 control chromosomes in the GnomAD database, including 308 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.016 (72 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (236 hom.)
• Consequence: ATAD3B NM_031921.6 splice_region, intron
• Scores: Splicing: ADA: 0.3048
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.28
• Publications: 7 publications found

Genes affected

ATAD3B (HGNC:24007): (ATPase family AAA domain containing 3B) The protein encoded by this gene is localized to the mitochondrial inner membrane, where it can bind to a highly-related protein, ATAD3A. ATAD3A appears to interact with matrix nucleoid complexes, and the encoded protein negatively regulates that interaction. This gene is expressed almost exclusively in pluripotent embryonic stem cells and some cancer cells. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0164 (2485/151910) while in subpopulation AFR AF = 0.041 (1697/41440). AF 95% confidence interval is 0.0393. There are 72 homozygotes in GnomAd4. There are 1239 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 72 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031921.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATAD3B	NM_031921.6	MANE Select	c.907-5G>A		splice_region intron	N/A	NP_114127.3
	ATAD3B	NM_001317238.2		c.769-5G>A		splice_region intron	N/A	NP_001304167.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATAD3B	ENST00000673477.1	MANE Select	c.907-5G>A		splice_region intron	N/A	ENSP00000500094.1
	ATAD3B	ENST00000308647.8	TSL:1	c.589-5G>A		splice_region intron	N/A	ENSP00000311766.8
	ATAD3B	ENST00000472194.6	TSL:1	n.1243-5G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2482 AN: 151794 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.0410

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00539

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00720

Gnomad OTH AF: 0.0149

GnomAD2 exomes AF: 0.00690 AC: 1711 AN: 248126 AF XY: 0.00638

Gnomad AFR exome AF: 0.0293

Gnomad AMR exome AF: 0.00444

Gnomad ASJ exome AF: 0.00742

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.00529

Gnomad OTH exome AF: 0.00661

GnomAD4 exome AF: 0.00751 AC: 10958 AN: 1458562 Hom.: 236 Cov.: 33 AF XY: 0.00715 AC XY: 5188 AN XY: 725584

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0359 AC: 1191 AN: 33184

American (AMR) AF: 0.00466 AC: 208 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00801 AC: 209 AN: 26090

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39690

South Asian (SAS) AF: 0.00215 AC: 185 AN: 86126

European-Finnish (FIN) AF: 0.0158 AC: 840 AN: 53284

Middle Eastern (MID) AF: 0.00142 AC: 8 AN: 5650

European-Non Finnish (NFE) AF: 0.00715 AC: 7930 AN: 1109640

Other (OTH) AF: 0.00632 AC: 381 AN: 60240

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0164 AC: 2485 AN: 151910 Hom.: 72 Cov.: 32 AF XY: 0.0167 AC XY: 1239 AN XY: 74238

African (AFR) AF: 0.0410 AC: 1697 AN: 41440

American (AMR) AF: 0.00538 AC: 82 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3466

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5152

South Asian (SAS) AF: 0.00209 AC: 10 AN: 4796

European-Finnish (FIN) AF: 0.0144 AC: 152 AN: 10590

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00717 AC: 487 AN: 67920

Other (OTH) AF: 0.0147 AC: 31 AN: 2108

Alfa AF: 0.00571 Hom.: 1

Bravo AF: 0.0172

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	18
DANN	Benign	0.63
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.30
dbscSNV1_RF	Benign	0.54
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 2

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

Other links and lift over

dbSNP: rs1622213; hg19: chr1-1421157;