chr3-124977881-C-T

Variant summary

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

The NM_020733.2(HEG1):​c.3799G>A​(p.Ala1267Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000144 in 1,575,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

HEG1
NM_020733.2 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.54
Variant links:
Genes affected
HEG1 (HGNC:29227): (heart development protein with EGF like domains 1) Predicted to enable calcium ion binding activity. Involved in several processes, including negative regulation of Rho protein signal transduction; negative regulation of Rho-dependent protein serine/threonine kinase activity; and negative regulation of membrane permeability. Located in cell-cell junction. [provided by Alliance of Genome Resources, Apr 2022]

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=0.18875459).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HEG1NM_020733.2 linkc.3799G>A p.Ala1267Thr missense_variant Exon 15 of 17 ENST00000311127.9 NP_065784.1 Q9ULI3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HEG1ENST00000311127.9 linkc.3799G>A p.Ala1267Thr missense_variant Exon 15 of 17 5 NM_020733.2 ENSP00000311502.3 Q9ULI3-1
HEG1ENST00000650592.2 linkc.4099G>A p.Ala1367Thr missense_variant Exon 16 of 18 ENSP00000515478.1 A0A994J6K3

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000103
AC:
20
AN:
193734
Hom.:
0
AF XY:
0.0000773
AC XY:
8
AN XY:
103444
show subpopulations
Gnomad AFR exome
AF:
0.000182
Gnomad AMR exome
AF:
0.000140
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:
0.000168
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000154
AC:
219
AN:
1423200
Hom.:
0
Cov.:
29
AF XY:
0.000153
AC XY:
108
AN XY:
704274
show subpopulations
Gnomad4 AFR exome
AF:
0.0000307
Gnomad4 AMR exome
AF:
0.000102
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000124
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000191
Gnomad4 OTH exome
AF:
0.0000678
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000975
Hom.:
0
Bravo
AF:
0.0000756
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000251
AC:
1
ESP6500EA
AF:
0.000240
AC:
2
ExAC
AF:
0.0000584
AC:
7

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 16, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3799G>A (p.A1267T) alteration is located in exon 15 (coding exon 15) of the HEG1 gene. This alteration results from a G to A substitution at nucleotide position 3799, causing the alanine (A) at amino acid position 1267 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
0.32
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;.
Eigen
Benign
-0.53
Eigen_PC
Benign
-0.43
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.80
T;T
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.19
T;T
MetaSVM
Uncertain
0.069
D
MutationAssessor
Benign
0.81
L;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-2.8
D;D
REVEL
Uncertain
0.35
Sift
Benign
0.040
D;D
Sift4G
Uncertain
0.049
D;D
Polyphen
0.10
B;.
Vest4
0.51
MVP
0.89
MPC
0.14
ClinPred
0.075
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.056
gMVP
0.76

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: rs201910585; hg19: chr3-124696725; COSMIC: COSV60762676; COSMIC: COSV60762676; API