chr11-94498143-C-T

Variant names:

• chr11-94498143-C-T
• rs370374382
• NM_017704.3:c.331C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.56

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]

ACMG classification

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
ANKRD49	NM_017704.3	c.331C>T	p.Pro111Ser	missense_variant	Exon 3 of 3	ENST00000544612.6	NP_060174.2
ANKRD49	XM_017017941.2	c.331C>T	p.Pro111Ser	missense_variant	Exon 3 of 3		XP_016873430.1
MRE11	XM_011542837.3	c.-105-5237G>A		intron_variant	Intron 1 of 19		XP_011541139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD49	ENST00000544612.6	c.331C>T	p.Pro111Ser	missense_variant	Exon 3 of 3	1	NM_017704.3	ENSP00000440396.1

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

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

Other links and lift over

dbSNP: rs370374382; hg19: chr11-94231309;