chr5-140485620-A-G

Variant names:

• chr5-140485620-A-G
• rs766829999
• NM_017747.3:c.2030A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. 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
• Publications: 0 publications found

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:33530): (ANKHD1-EIF4EBP3 readthrough) The ANKHD1-EIF4EBP3 mRNA is an infrequent but naturally occurring readthrough transcript of the neighboring ANKHD1 and EIF4EBP3 genes. This readthrough transcript encodes a protein composed mostly of the multiple ankyrin repeats, single KH-domain protein, with its C-terminus encoded in a different reading frame from the shared portion of the EIF4EBP3 gene. The significance of this readthrough mRNA and the function of its protein product have not yet been determined. [provided by RefSeq, Nov 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15985796).
• BS2: High AC in GnomAdExome4 at 59 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017747.3. 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
	ANKHD1	NM_017747.3	MANE Select	c.2030A>G	p.Lys677Arg	missense	Exon 13 of 34	NP_060217.1	Q8IWZ3-1
	ANKHD1-EIF4EBP3	NM_020690.6		c.2030A>G	p.Lys677Arg	missense	Exon 13 of 36	NP_065741.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKHD1	ENST00000360839.7	TSL:1 MANE Select	c.2030A>G	p.Lys677Arg	missense	Exon 13 of 34	ENSP00000354085.2	Q8IWZ3-1
	ANKHD1-EIF4EBP3	ENST00000532219.5	TSL:2	c.2030A>G	p.Lys677Arg	missense	Exon 13 of 36	ENSP00000432016.1
	ANKHD1	ENST00000936090.1		c.2030A>G	p.Lys677Arg	missense	Exon 13 of 34	ENSP00000606149.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000109 AC: 27 AN: 248838 AF XY: 0.0000817

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000559 AC: 25 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111962

Other (OTH) AF: 0.0000994 AC: 6 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000906 AC: 11

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.010	N
PhyloP100		9.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.41
Sift	Benign	0.15	T
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.56
MutPred		0.40		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
Mutation Taster		=45/55	disease causing

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

Other links and lift over

dbSNP: rs766829999; hg19: chr5-139865205;