chr16-727996-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_032304.4(HAGHL):​c.137C>T​(p.Ser46Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

HAGHL
NM_032304.4 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.283
Variant links:
Genes affected
HAGHL (HGNC:14177): (hydroxyacylglutathione hydrolase like) Predicted to enable hydroxyacylglutathione hydrolase activity and metal ion binding activity. Predicted to be involved in methylglyoxal catabolic process to D-lactate via S-lactoyl-glutathione. [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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.35944158).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HAGHLNM_032304.4 linkuse as main transcriptc.137C>T p.Ser46Phe missense_variant 2/8 ENST00000389703.8 NP_115680.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HAGHLENST00000389703.8 linkuse as main transcriptc.137C>T p.Ser46Phe missense_variant 2/81 NM_032304.4 ENSP00000374353 P1Q6PII5-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
6.87e-7
AC:
1
AN:
1455472
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
724082
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
9.01e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 20, 2024The c.137C>T (p.S46F) alteration is located in exon 2 (coding exon 2) of the HAGHL gene. This alteration results from a C to T substitution at nucleotide position 137, causing the serine (S) at amino acid position 46 to be replaced by a phenylalanine (F). 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
0.20
BayesDel_addAF
Benign
0.0035
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.65
.;D;.;.;D;.;D;.;D
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.33
FATHMM_MKL
Benign
0.076
N
LIST_S2
Benign
0.83
.;T;D;T;T;D;T;D;D
M_CAP
Pathogenic
0.33
D
MetaRNN
Benign
0.36
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.51
T
MutationAssessor
Uncertain
2.3
M;M;M;.;.;M;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-3.7
D;D;D;D;D;D;.;D;D
REVEL
Uncertain
0.30
Sift
Uncertain
0.0020
D;D;D;D;D;D;.;D;D
Sift4G
Uncertain
0.013
D;T;D;T;D;D;D;D;D
Polyphen
0.96
D;P;D;.;P;P;.;.;.
Vest4
0.34
MutPred
0.46
Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);.;
MVP
0.62
MPC
0.22
ClinPred
0.69
D
GERP RS
2.4
Varity_R
0.10
gMVP
0.20

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-777996; API