1-2529522-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001010926.4(HES5):​c.448G>A​(p.Ala150Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,050,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A150D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

HES5
NM_001010926.4 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.156
Variant links:
Genes affected
HES5 (HGNC:19764): (hes family bHLH transcription factor 5) This gene encodes a member of a family of basic helix-loop-helix transcriptional repressors. The protein product of this gene, which is activated downstream of the Notch pathway, regulates cell differentiation in multiple tissues. Disruptions in the normal expression of this gene have been associated with developmental diseases and cancer. [provided by RefSeq, Dec 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.10827747).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HES5NM_001010926.4 linkc.448G>A p.Ala150Thr missense_variant Exon 3 of 3 ENST00000378453.4 NP_001010926.1 Q5TA89
HES5XM_005244751.5 linkc.544G>A p.Ala182Thr missense_variant Exon 2 of 2 XP_005244808.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HES5ENST00000378453.4 linkc.448G>A p.Ala150Thr missense_variant Exon 3 of 3 1 NM_001010926.4 ENSP00000367714.3 Q5TA89

Frequencies

GnomAD3 genomes
AF:
0.000170
AC:
25
AN:
147464
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000588
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000675
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
GnomAD4 exome
AF:
0.0000321
AC:
29
AN:
902984
Hom.:
0
Cov.:
27
AF XY:
0.0000379
AC XY:
16
AN XY:
422270
show subpopulations
Gnomad4 AFR exome
AF:
0.000459
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000131
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000242
Gnomad4 NFE exome
AF:
0.0000211
Gnomad4 OTH exome
AF:
0.0000314
GnomAD4 genome
AF:
0.000169
AC:
25
AN:
147570
Hom.:
0
Cov.:
33
AF XY:
0.000139
AC XY:
10
AN XY:
71946
show subpopulations
Gnomad4 AFR
AF:
0.000586
Gnomad4 AMR
AF:
0.0000674
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
Alfa
AF:
0.000142
Hom.:
0

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Mar 08, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.448G>A (p.A150T) alteration is located in exon 3 (coding exon 3) of the HES5 gene. This alteration results from a G to A substitution at nucleotide position 448, causing the alanine (A) at amino acid position 150 to be replaced by a threonine (T). 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
0.079
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
6.7
DANN
Benign
0.91
DEOGEN2
Benign
0.20
T
Eigen
Benign
-0.89
Eigen_PC
Benign
-0.94
FATHMM_MKL
Benign
0.085
N
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.14
N
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
0.33
N
REVEL
Benign
0.13
Sift
Benign
0.42
T
Sift4G
Benign
0.61
T
Polyphen
0.72
P
Vest4
0.12
MutPred
0.21
Gain of glycosylation at A150 (P = 0.0012);
MVP
0.27
MPC
0.13
ClinPred
0.19
T
GERP RS
1.1
Varity_R
0.065
gMVP
0.45

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: rs937587295; hg19: chr1-2460961; API