5-75091401-C-T

Variant summary

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

The NM_001372053.1(ANKRD31):​c.5332G>A​(p.Glu1778Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 1,520,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

ANKRD31
NM_001372053.1 missense, splice_region

Scores

9
10
Splicing: ADA: 0.9874
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.55
Variant links:
Genes affected
ANKRD31 (HGNC:26853): (ankyrin repeat domain 31) This gene encodes a protein containing multiple ankyrin repeats. Ankyrin domains function in protein-protein interactions in a variety of cellular processes. Mutations in this gene are associated with a Rett syndrome (RTT)-like phenotype. [provided by RefSeq, Apr 2017]

Genome browser will be placed here

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
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANKRD31NM_001372053.1 linkc.5332G>A p.Glu1778Lys missense_variant, splice_region_variant Exon 23 of 26 ENST00000506364.6 NP_001358982.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANKRD31ENST00000506364.6 linkc.5332G>A p.Glu1778Lys missense_variant, splice_region_variant Exon 23 of 26 5 NM_001372053.1 ENSP00000427262.2 D6RJB7

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
151988
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000793
AC:
1
AN:
126098
Hom.:
0
AF XY:
0.0000148
AC XY:
1
AN XY:
67582
show subpopulations
Gnomad AFR exome
AF:
0.000136
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
7.31e-7
AC:
1
AN:
1368192
Hom.:
0
Cov.:
31
AF XY:
0.00000148
AC XY:
1
AN XY:
674562
show subpopulations
Gnomad4 AFR exome
AF:
0.0000328
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
151988
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74234
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 24, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.5161G>A (p.E1721K) alteration is located in exon 22 (coding exon 22) of the ANKRD31 gene. This alteration results from a G to A substitution at nucleotide position 5161, causing the glutamic acid (E) at amino acid position 1721 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
Benign
0.19
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.023
.;T
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.86
D;D
M_CAP
Uncertain
0.086
D
MetaRNN
Benign
0.19
T;T
MetaSVM
Uncertain
-0.27
T
MutationAssessor
Uncertain
2.0
.;M
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.2
.;N
REVEL
Benign
0.15
Sift
Uncertain
0.0030
.;D
Sift4G
Uncertain
0.019
D;D
Vest4
0.43
MutPred
0.42
.;Loss of ubiquitination at K1725 (P = 0.0246);
MVP
0.40
ClinPred
0.61
D
GERP RS
4.4
Varity_R
0.22
gMVP
0.21

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.73
SpliceAI score (max)
0.42
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.42
Position offset: 0

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: rs1289686779; hg19: chr5-74387226; API