Variant 11-94496948-T-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_017704.3(ANKRD49):c.255T>A(p.Asn85Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

ANKRD49
NM_017704.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.64

Variant links:

Genes affected

ANKRD49 (HGNC:25970): (ankyrin repeat domain 49) Involved in positive regulation of transcription, DNA-templated. Predicted to be located in nucleus. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ANKRD49 links:

MRE11 (HGNC:7230): (MRE11 homolog, double strand break repair nuclease) This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

MRE11 links:

ANKRD49 (HGNC:):

ANKRD49 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD49	NM_017704.3 linkuse as main transcript	c.255T>A	p.Asn85Lys	missense_variant	2/3	ENST00000544612.6	NP_060174.2	Q8WVL7A0A024R398
ANKRD49	XM_017017941.2 linkuse as main transcript	c.255T>A	p.Asn85Lys	missense_variant	2/3		XP_016873430.1	Q8WVL7A0A024R398
MRE11	XM_011542837.3 linkuse as main transcript	c.-105-4042A>T		intron_variant			XP_011541139.1	P49959-1A0A024R395

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD49	ENST00000544612.6 linkuse as main transcript	c.255T>A	p.Asn85Lys	missense_variant	2/3	1	NM_017704.3	ENSP00000440396.1		Q8WVL7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000410

AC:

AN:

244000

Hom.:

AF XY:

0.00000751

AC XY:

AN XY:

133076

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000914

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460446

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726564

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000529

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.255T>A (p.N85K) alteration is located in exon 2 (coding exon 1) of the ANKRD49 gene. This alteration results from a T to A substitution at nucleotide position 255, causing the asparagine (N) at amino acid position 85 to be replaced by a lysine (K). 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

0.62

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.;T;.;.;T

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

.;.;T;T;T;D

M_CAP

Benign

0.073

MetaRNN

Uncertain

0.52

D;D;D;D;D;D

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.4

L;.;.;.;.;L

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.8

D;D;D;D;D;D

REVEL

Uncertain

0.34

Sift

Benign

0.035

D;D;D;D;D;D

Sift4G

Benign

0.065

T;D;D;D;D;T

Polyphen

0.91

P;D;.;D;.;P

Vest4

0.68

MutPred

0.59

Gain of methylation at N85 (P = 0.0067);Gain of methylation at N85 (P = 0.0067);Gain of methylation at N85 (P = 0.0067);Gain of methylation at N85 (P = 0.0067);Gain of methylation at N85 (P = 0.0067);Gain of methylation at N85 (P = 0.0067);

MVP

0.59

MPC

1.1

ClinPred

0.97

GERP RS

4.9

Varity_R

0.46

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over