5-140526166-C-T

Position:

• chr5-140526166-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017747.3(ANKHD1):​c.4663C>T​(p.Pro1555Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANKHD1 NM_017747.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.81

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13200727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKHD1	NM_017747.3	c.4663C>T	p.Pro1555Ser	missense_variant	26/34	ENST00000360839.7	NP_060217.1
ANKHD1-EIF4EBP3	NM_020690.6	c.4663C>T	p.Pro1555Ser	missense_variant	26/36		NP_065741.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKHD1	ENST00000360839.7	c.4663C>T	p.Pro1555Ser	missense_variant	26/34	1	NM_017747.3	ENSP00000354085.2
ANKHD1-EIF4EBP3	ENST00000532219.5	c.4663C>T	p.Pro1555Ser	missense_variant	26/36	2		ENSP00000432016.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461352 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727006

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 05, 2022

The c.4663C>T (p.P1555S) alteration is located in exon 26 (coding exon 26) of the ANKHD1-EIF4EBP3 gene. This alteration results from a C to T substitution at nucleotide position 4663, causing the proline (P) at amino acid position 1555 to be replaced by a serine (S). 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	Benign	0.063
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.016	T;T;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	D;D;T;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.34	N;N;N;N
REVEL	Benign	0.095
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.049
MutPred		0.10		Loss of catalytic residue at P1554 (P = 0.0107);.;.;Loss of catalytic residue at P1554 (P = 0.0107);
MVP		0.29
MPC		0.32
ClinPred		0.36	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.30

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: chr5-139905751;