4-73076278-G-C

Position:

• chr4-73076278-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_032217.5(ANKRD17):​c.7765C>G​(p.Pro2589Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0013 in 1,609,220 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: ANKRD17 NM_032217.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 6.42

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 Benign. Variant got -8 ACMG points.

• 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=0.018128008).
• BP6: Variant 4-73076278-G-C is Benign according to our data. Variant chr4-73076278-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3044401.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 119 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD17	NM_032217.5	c.7765C>G	p.Pro2589Ala	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.7765C>G	p.Pro2589Ala	missense_variant	34/34	5	NM_032217.5	ENSP00000351416.4
ANKRD17	ENST00000509867.6	c.7426C>G	p.Pro2476Ala	missense_variant	34/34	1		ENSP00000427151.2
ANKRD17	ENST00000558247.5	c.7414C>G	p.Pro2472Ala	missense_variant	34/34	1		ENSP00000453434.1
ANKRD17	ENST00000330838.10	c.7012C>G	p.Pro2338Ala	missense_variant	33/33	2		ENSP00000332265.6

Frequencies

GnomAD3 genomes AF: 0.000784 AC: 119 AN: 151852 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000475

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000866 AC: 214 AN: 247134 Hom.: 0 AF XY: 0.000920 AC XY: 123 AN XY: 133764

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000238

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000166

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.00136 AC: 1976 AN: 1457250 Hom.: 2 Cov.: 30 AF XY: 0.00124 AC XY: 897 AN XY: 724970

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.000181

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000187

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00169

Gnomad4 OTH exome AF: 0.000981

GnomAD4 genome AF: 0.000783 AC: 119 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.000700 AC XY: 52 AN XY: 74252

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000475

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.000971

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000914 AC: 111

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ANKRD17-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.081
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.65	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0080	B;.;.
Vest4		0.25
MVP		0.31
MPC		0.29
ClinPred		0.017	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.25

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: rs144043898; hg19: chr4-73941995;