NM_032217.5:c.7744C>A

Variant names:

• chr4-73076948-G-T
• rs1293178841
• NM_032217.5:c.7744C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_032217.5(ANKRD17):​c.7744C>A​(p.Pro2582Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,610,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ANKRD17 NM_032217.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.51

Genes affected

ANKRD17 (HGNC:23575): (ankyrin repeat domain 17) The protein encoded by this gene belongs to the family of ankyrin repeat-containing proteins, and contains two distinct arrays of ankyrin repeats in its amino-terminal region, one with 15 ankyrin repeats, and the other with 10 ankyrin repeats. It also contains a nuclear export signal, nuclear localization signal, and a cyclin-binding RXL motif. Localization of this protein to the nucleus has been shown experimentally, and interactions between this protein and cyclin-dependent kinase 2 have been observed. It has been suggested that this protein plays a role in both DNA replication and in both anti-viral and anti-bacterial innate immune pathways. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ANKRD17 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 5.3588 (above the threshold of 3.09). Trascript score misZ: 6.9945 (above the threshold of 3.09). GenCC associations: The gene is linked to syndromic intellectual disability, Chopra-Amiel-Gordon syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38505137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD17	NM_032217.5	c.7744C>A	p.Pro2582Thr	missense_variant	Exon 33 of 34	ENST00000358602.9	NP_115593.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD17	ENST00000358602.9	c.7744C>A	p.Pro2582Thr	missense_variant	Exon 33 of 34	5	NM_032217.5	ENSP00000351416.4
ANKRD17	ENST00000509867.6	c.7405C>A	p.Pro2469Thr	missense_variant	Exon 33 of 34	1		ENSP00000427151.2
ANKRD17	ENST00000558247.5	c.7393C>A	p.Pro2465Thr	missense_variant	Exon 33 of 34	1		ENSP00000453434.1
ANKRD17	ENST00000330838.10	c.6991C>A	p.Pro2331Thr	missense_variant	Exon 32 of 33	2		ENSP00000332265.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152100 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457932 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725114

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152100 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74288

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7744C>A (p.P2582T) alteration is located in exon 33 (coding exon 33) of the ANKRD17 gene. This alteration results from a C to A substitution at nucleotide position 7744, causing the proline (P) at amino acid position 2582 to be replaced by a threonine (T). 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	Benign	0.078
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.8	L;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.54
MutPred		0.24		Gain of sheet (P = 0.0344);.;.;
MVP		0.52
MPC		0.34
ClinPred		0.69	D
GERP RS		5.8
Varity_R		0.16
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs1293178841; hg19: chr4-73942665;