14-61736925-A-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001530.4(HIF1A):c.1065A>T(p.Gln355His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,613,998 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 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00016 ( 0 hom. )
Consequence
HIF1A
NM_001530.4 missense
NM_001530.4 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 2.06
Genes affected
HIF1A (HGNC:4910): (hypoxia inducible factor 1 subunit alpha) This gene encodes the alpha subunit of transcription factor hypoxia-inducible factor-1 (HIF-1), which is a heterodimer composed of an alpha and a beta subunit. HIF-1 functions as a master regulator of cellular and systemic homeostatic response to hypoxia by activating transcription of many genes, including those involved in energy metabolism, angiogenesis, apoptosis, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. HIF-1 thus plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2011]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAd at 21 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HIF1A | NM_001530.4 | c.1065A>T | p.Gln355His | missense_variant | 9/15 | ENST00000337138.9 | |
HIF1A-AS3 | NR_144368.1 | n.213+13960T>A | intron_variant, non_coding_transcript_variant | ||||
HIF1A | NM_001243084.2 | c.1137A>T | p.Gln379His | missense_variant | 9/15 | ||
HIF1A | NM_181054.3 | c.1065A>T | p.Gln355His | missense_variant | 9/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HIF1A | ENST00000337138.9 | c.1065A>T | p.Gln355His | missense_variant | 9/15 | 1 | NM_001530.4 | P4 | |
HIF1A-AS3 | ENST00000660325.2 | n.215+13960T>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 152164Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
21
AN:
152164
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251276Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135824
GnomAD3 exomes
AF:
AC:
23
AN:
251276
Hom.:
AF XY:
AC XY:
9
AN XY:
135824
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000163 AC: 238AN: 1461716Hom.: 0 Cov.: 31 AF XY: 0.000166 AC XY: 121AN XY: 727160
GnomAD4 exome
AF:
AC:
238
AN:
1461716
Hom.:
Cov.:
31
AF XY:
AC XY:
121
AN XY:
727160
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000138 AC: 21AN: 152282Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74456
GnomAD4 genome
?
AF:
AC:
21
AN:
152282
Hom.:
Cov.:
33
AF XY:
AC XY:
12
AN XY:
74456
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
?
AF:
AC:
6
EpiCase
AF:
EpiControl
AF:
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 submitter | clinical testing | Ambry Genetics | Jul 14, 2021 | The c.1065A>T (p.Q355H) alteration is located in exon 9 (coding exon 9) of the HIF1A gene. This alteration results from a A to T substitution at nucleotide position 1065, causing the glutamine (Q) at amino acid position 355 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;T;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N
REVEL
Benign
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
P;P;.;.;.
Vest4
MutPred
0.43
.;Gain of catalytic residue at L355 (P = 0.1622);.;.;.;
MVP
MPC
1.3
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 8
Find out detailed SpliceAI scores and Pangolin per-transcript scores at