5-140485620-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_017747.3(ANKHD1):c.2030A>G(p.Lys677Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000404 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: ANKHD1 NM_017747.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.25

Genes affected

ANKHD1 (HGNC:24714): (ankyrin repeat and KH domain containing 1) This gene encodes a protein with multiple ankyrin repeat domains and a single KH-domain. The protein is thought to function as a scaffolding protein, and it may be involved in the regulation of caspases and thereby play an antiapoptotic role in cell survival. Alternative splicing results in multiple transcript variants, one of which generates a fusion transcript (MASK-BP3) with the downstream eIF4E-binding protein 3 (EIF4EBP3) gene, resulting in a protein comprised of the ANKHD1 sequence for the majority of the protein and a different C-terminus due to an alternate reading frame for the EIF4EBP3 segments. [provided by RefSeq, Sep 2010]

ANKHD1-EIF4EBP3 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ANKHD1
• BP4: Computational evidence support a benign effect (MetaRNN=0.15985796).
• BS2: High AC in GnomAdExome at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKHD1	NM_017747.3	c.2030A>G	p.Lys677Arg	missense_variant	13/34	ENST00000360839.7
ANKHD1-EIF4EBP3	NM_020690.6	c.2030A>G	p.Lys677Arg	missense_variant	13/36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKHD1	ENST00000360839.7	c.2030A>G	p.Lys677Arg	missense_variant	13/34	1	NM_017747.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.000109 AC: 27 AN: 248838 Hom.: 0 AF XY: 0.0000817 AC XY: 11 AN XY: 134714

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000450

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461760 Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000302

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.2030A>G (p.K677R) alteration is located in exon 13 (coding exon 13) of the ANKHD1 gene. This alteration results from a A to G substitution at nucleotide position 2030, causing the lysine (K) at amino acid position 677 to be replaced by an arginine (R). 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	Pathogenic	0.85
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.010	N;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	D;D;N;D
REVEL	Uncertain	0.41
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		1.0	D;D;.;.
Vest4		0.56
MutPred		0.40		Loss of ubiquitination at K677 (P = 0.0199);.;.;Loss of ubiquitination at K677 (P = 0.0199);
MVP		0.60
MPC		0.52
ClinPred		0.19	T
GERP RS		5.4
Varity_R		0.29
gMVP		0.33

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: rs766829999; hg19: chr5-139865205;