4-73076253-A-G

Position:

• chr4-73076253-A-G

Variant summary

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

The NM_032217.5(ANKRD17):​c.7790T>C​(p.Val2597Ala) 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 gene, where missense usually causes diseases (based on misZ statistic), ANKRD17. . Gene score misZ 5.3588 (greater than the threshold 3.09). Trascript score misZ 6.9945 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, Chopra-Amiel-Gordon syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3721264).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD17	NM_032217.5	c.7790T>C	p.Val2597Ala	missense_variant	34/34	ENST00000358602.9	NP_115593.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD17	ENST00000358602.9	c.7790T>C	p.Val2597Ala	missense_variant	34/34	5	NM_032217.5	ENSP00000351416.4
ANKRD17	ENST00000509867.6	c.7451T>C	p.Val2484Ala	missense_variant	34/34	1		ENSP00000427151.2
ANKRD17	ENST00000558247.5	c.7439T>C	p.Val2480Ala	missense_variant	34/34	1		ENSP00000453434.1
ANKRD17	ENST00000330838.10	c.7037T>C	p.Val2346Ala	missense_variant	33/33	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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.90	L;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.77	P;.;.
Vest4		0.58
MutPred		0.23		Loss of catalytic residue at V2597 (P = 0.034);.;.;
MVP		0.59
MPC		0.36
ClinPred		0.81	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.42

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: chr4-73941970;