17-36953808-C-G

Variant names:

• chr17-36953808-C-G
• rs1054553638
• NM_012138.4:c.733C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012138.4(AATF):​c.733C>G​(p.Gln245Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: AATF NM_012138.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

Genes affected

AATF (HGNC:19235): (apoptosis antagonizing transcription factor) The protein encoded by this gene was identified on the basis of its interaction with MAP3K12/DLK, a protein kinase known to be involved in the induction of cell apoptosis. This gene product contains a leucine zipper, which is a characteristic motif of transcription factors, and was shown to exhibit strong transactivation activity when fused to Gal4 DNA binding domain. Overexpression of this gene interfered with MAP3K12 induced apoptosis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AATF	NM_012138.4	c.733C>G	p.Gln245Glu	missense_variant	Exon 4 of 12	ENST00000619387.5	NP_036270.1
AATF	NM_001411094.1	c.733C>G	p.Gln245Glu	missense_variant	Exon 4 of 11		NP_001398023.1
AATF	XM_047435748.1	c.733C>G	p.Gln245Glu	missense_variant	Exon 4 of 5		XP_047291704.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AATF	ENST00000619387.5	c.733C>G	p.Gln245Glu	missense_variant	Exon 4 of 12	1	NM_012138.4	ENSP00000477848.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.733C>G (p.Q245E) alteration is located in exon 4 (coding exon 4) of the AATF gene. This alteration results from a C to G substitution at nucleotide position 733, causing the glutamine (Q) at amino acid position 245 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.5	H
PrimateAI	Uncertain	0.69	T
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.78		Loss of MoRF binding (P = 0.0731);
MVP		0.75
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1054553638; hg19: chr17-35311108;