chr4-73076265-T-G

Variant names:

• chr4-73076265-T-G
• NM_032217.5:c.7778A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_032217.5(ANKRD17):​c.7778A>C​(p.His2593Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANKRD17 NM_032217.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.46

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 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD17	NM_032217.5	c.7778A>C	p.His2593Pro	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.7778A>C	p.His2593Pro	missense_variant	Exon 34 of 34	5	NM_032217.5	ENSP00000351416.4
ANKRD17	ENST00000509867.6	c.7439A>C	p.His2480Pro	missense_variant	Exon 34 of 34	1		ENSP00000427151.2
ANKRD17	ENST00000558247.5	c.7427A>C	p.His2476Pro	missense_variant	Exon 34 of 34	1		ENSP00000453434.1
ANKRD17	ENST00000330838.10	c.7025A>C	p.His2342Pro	missense_variant	Exon 33 of 33	2		ENSP00000332265.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459482 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726096

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: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.55	D;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.97	L;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0040	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.73
MutPred		0.59		Gain of disorder (P = 0.0245);.;.;
MVP		0.74
MPC		0.49
ClinPred		0.93	D
GERP RS		5.3
Varity_R		0.49
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: chr4-73941982;