rs377228484

Variant names:

• chr1-1452433-C-G
• rs377228484
• NM_001039211.3:c.221C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-1452433-C-G
• chr1-1452433-C-A
• chr1-1452433-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001039211.3(ATAD3C):​c.221C>G​(p.Thr74Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000031 in 1,613,568 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (1 hom.)
• Consequence: ATAD3C NM_001039211.3 missense, splice_region
• Scores: Splicing: ADA: 0.003879
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13
• Publications: 3 publications found

Genes affected

ATAD3C (HGNC:32151): (ATPase family AAA domain containing 3C) Predicted to enable zinc ion binding activity. Predicted to be involved in mitochondrion organization. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ATAD3C Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039211.3. 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
	ATAD3C	NM_001039211.3	MANE Select	c.221C>G	p.Thr74Arg	missense splice_region	Exon 3 of 12	NP_001034300.2	Q5T2N8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATAD3C	ENST00000378785.7	TSL:2 MANE Select	c.221C>G	p.Thr74Arg	missense splice_region	Exon 3 of 12	ENSP00000368062.2	Q5T2N8
	ATAD3C	ENST00000475091.2	TSL:5	c.221C>G	p.Thr74Arg	missense splice_region	Exon 4 of 6	ENSP00000464661.1	J3QSF3

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152028 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251346 AF XY: 0.0000368

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461540 Hom.: 1 Cov.: 33 AF XY: 0.0000275 AC XY: 20 AN XY: 727058

African (AFR) AF: 0.000657 AC: 22 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111762

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152028 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74254

African (AFR) AF: 0.000290 AC: 12 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15226

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000565 Hom.: 1

Bravo AF: 0.000110

ESP6500AA AF: 0.00145 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Benign	0.76
DEOGEN2	Benign	0.046	T
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.059	T
Polyphen		1.0	D
Vest4		0.93
MVP		0.91
MPC		0.65
ClinPred		0.67	D
GERP RS		2.5
Varity_R		0.93
gMVP		0.45
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0039
dbscSNV1_RF	Benign	0.074
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 1

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

Other links and lift over

dbSNP: rs377228484; hg19: chr1-1387813;