4-73077533-T-C

Variant names:

• chr4-73077533-T-C
• rs1721118591
• NM_032217.5:c.7409A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032217.5(ANKRD17):​c.7409A>G​(p.Asp2470Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000256 in 1,559,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ANKRD17 NM_032217.5 missense, splice_region
• Scores: Splicing: ADA: 0.0001286
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.49
• Publications: 0 publications found

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]

ANKRD17 Gene-Disease associations (from GenCC):

• syndromic complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Chopra-Amiel-Gordon syndrome

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19885212).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032217.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD17	NM_032217.5	MANE Select	c.7409A>G	p.Asp2470Gly	missense splice_region	Exon 32 of 34	NP_115593.3
	ANKRD17	NM_015574.2		c.7406A>G	p.Asp2469Gly	missense splice_region	Exon 32 of 34	NP_056389.1	O75179-2
	ANKRD17	NM_001286771.3		c.7070A>G	p.Asp2357Gly	missense splice_region	Exon 32 of 34	NP_001273700.1	O75179-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD17	ENST00000358602.9	TSL:5 MANE Select	c.7409A>G	p.Asp2470Gly	missense splice_region	Exon 32 of 34	ENSP00000351416.4	O75179-1
	ANKRD17	ENST00000509867.6	TSL:1	c.7070A>G	p.Asp2357Gly	missense splice_region	Exon 32 of 34	ENSP00000427151.2	O75179-7
	ANKRD17	ENST00000558247.5	TSL:1	c.7058A>G	p.Asp2353Gly	missense splice_region	Exon 32 of 34	ENSP00000453434.1	H0YM23

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 7.11e-7 AC: 1 AN: 1407444 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 697140

African (AFR) AF: 0.00 AC: 0 AN: 30940

American (AMR) AF: 0.00 AC: 0 AN: 32788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23832

East Asian (EAS) AF: 0.00 AC: 0 AN: 38186

South Asian (SAS) AF: 0.00 AC: 0 AN: 77314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5490

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088480

Other (OTH) AF: 0.0000172 AC: 1 AN: 57972

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

African (AFR) AF: 0.0000483 AC: 2 AN: 41444

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000937 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	ANKRD17-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Benign	0.29
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.41	N
PhyloP100		6.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.22	T
Polyphen		0.99	D
Vest4		0.45
MutPred		0.32		Gain of sheet (P = 0.0166)
MVP		0.58
MPC		0.40
ClinPred		0.58	D
GERP RS		4.5
Varity_R		0.25
gMVP		0.85
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.020
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

Other links and lift over

dbSNP: rs1721118591; hg19: chr4-73943250;