chr4-73076247-A-G

Variant names:

• chr4-73076247-A-G
• NM_032217.5:c.7796T>C

Variant summary

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

The NM_032217.5(ANKRD17):​c.7796T>C​(p.Met2599Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANKRD17 NM_032217.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.70

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=0.3226074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD17	NM_032217.5	c.7796T>C	p.Met2599Thr	missense_variant	Exon 34 of 34	ENST00000358602.9	NP_115593.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD17	ENST00000358602.9	c.7796T>C	p.Met2599Thr	missense_variant	Exon 34 of 34	5	NM_032217.5	ENSP00000351416.4
ANKRD17	ENST00000509867.6	c.7457T>C	p.Met2486Thr	missense_variant	Exon 34 of 34	1		ENSP00000427151.2
ANKRD17	ENST00000558247.5	c.7445T>C	p.Met2482Thr	missense_variant	Exon 34 of 34	1		ENSP00000453434.1
ANKRD17	ENST00000330838.10	c.7043T>C	p.Met2348Thr	missense_variant	Exon 33 of 33	2		ENSP00000332265.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7796T>C (p.M2599T) alteration is located in exon 34 (coding exon 34) of the ANKRD17 gene. This alteration results from a T to C substitution at nucleotide position 7796, causing the methionine (M) at amino acid position 2599 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	Uncertain	0.37
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.55	N;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.85	N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.44	B;.;.
Vest4		0.53
MutPred		0.23		Gain of catalytic residue at M2599 (P = 0.0549);.;.;
MVP		0.62
MPC		0.38
ClinPred		0.67	D
GERP RS		5.3
Varity_R		0.57
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-73941964;