chr11-94498143-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_017704.3(ANKRD49):​c.331C>T​(p.Pro111Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ANKRD49
NM_017704.3 missense

Scores

5
11
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.56
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANKRD49NM_017704.3 linkc.331C>T p.Pro111Ser missense_variant Exon 3 of 3 ENST00000544612.6 NP_060174.2 Q8WVL7A0A024R398
ANKRD49XM_017017941.2 linkc.331C>T p.Pro111Ser missense_variant Exon 3 of 3 XP_016873430.1 Q8WVL7A0A024R398
MRE11XM_011542837.3 linkc.-105-5237G>A intron_variant Intron 1 of 19 XP_011541139.1 P49959-1A0A024R395

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANKRD49ENST00000544612.6 linkc.331C>T p.Pro111Ser missense_variant Exon 3 of 3 1 NM_017704.3 ENSP00000440396.1 Q8WVL7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000113
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 28, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.331C>T (p.P111S) alteration is located in exon 3 (coding exon 2) of the ANKRD49 gene. This alteration results from a C to T substitution at nucleotide position 331, causing the proline (P) at amino acid position 111 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
Pathogenic
0.68
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.21
T;T;T;T
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.97
.;D;T;D
M_CAP
Uncertain
0.092
D
MetaRNN
Uncertain
0.72
D;D;D;D
MetaSVM
Uncertain
0.13
D
MutationAssessor
Benign
2.0
M;.;.;M
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-4.3
D;D;D;D
REVEL
Uncertain
0.58
Sift
Uncertain
0.013
D;T;D;D
Sift4G
Uncertain
0.026
D;T;D;D
Polyphen
0.89
P;.;.;P
Vest4
0.71
MVP
0.75
MPC
1.1
ClinPred
0.98
D
GERP RS
4.2
Varity_R
0.52
gMVP
0.83

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.

Other links and lift over

dbSNP: rs370374382; hg19: chr11-94231309; API