14-61738090-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001530.4(HIF1A):c.1253C>T(p.Thr418Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00564 in 1,592,204 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 38 hom. )

Consequence

HIF1A
NM_001530.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.51

Publications

33 publications found

Variant links:

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]

HIF1A links:

HIF1A-AS3 (HGNC:):

HIF1A-AS3 links:

HIF1A-AS3 (HGNC:54284): (HIF1A antisense RNA 3)

HIF1A-AS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006364763).

BP6

Variant 14-61738090-C-T is Benign according to our data. Variant chr14-61738090-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 777435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 617 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HIF1A	NM_001530.4 link	c.1253C>T	p.Thr418Ile	missense_variant	Exon 10 of 15	ENST00000337138.9	NP_001521.1
HIF1A	NM_001243084.2 link	c.1325C>T	p.Thr442Ile	missense_variant	Exon 10 of 15		NP_001230013.1
HIF1A	NM_181054.3 link	c.1253C>T	p.Thr418Ile	missense_variant	Exon 10 of 14		NP_851397.1
HIF1A-AS3	NR_144368.1 link	n.213+12795G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HIF1A	ENST00000337138.9 link	c.1253C>T	p.Thr418Ile	missense_variant	Exon 10 of 15	1	NM_001530.4	ENSP00000338018.4

Frequencies

GnomAD3 genomes

AF:

0.00407

AC:

617

AN:

151686

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00148

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00722

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.000574

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00584

Gnomad OTH

AF:

0.0101

GnomAD2 exomes

AF:

0.00384

AC:

897

AN:

233808

AF XY:

0.00391

show subpopulations

Gnomad AFR exome

AF:

0.00138

Gnomad AMR exome

AF:

0.00501

Gnomad ASJ exome

AF:

0.00210

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000767

Gnomad NFE exome

AF:

0.00610

Gnomad OTH exome

AF:

0.00428

GnomAD4 exome

AF:

0.00581

AC:

8366

AN:

1440412

Hom.:

Cov.:

AF XY:

0.00569

AC XY:

4073

AN XY:

715374

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

32464

American (AMR)

AF:

0.00485

AC:

198

AN:

40816

Ashkenazi Jewish (ASJ)

AF:

0.00169

AC:

AN:

24800

East Asian (EAS)

AF:

0.00

AC:

AN:

39554

South Asian (SAS)

AF:

0.000458

AC:

AN:

82918

European-Finnish (FIN)

AF:

0.000721

AC:

AN:

52740

Middle Eastern (MID)

AF:

0.00727

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

0.00694

AC:

7652

AN:

1102112

Other (OTH)

AF:

0.00544

AC:

323

AN:

59366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

341

682

1022

1363

1704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

306

612

918

1224

1530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00406

AC:

617

AN:

151792

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

278

AN XY:

74160

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

41394

American (AMR)

AF:

0.00721

AC:

110

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000624

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.000574

AC:

AN:

10450

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00584

AC:

397

AN:

67936

Other (OTH)

AF:

0.00996

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00541

Hom.:

Bravo

AF:

0.00451

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00358

AC:

435

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 07, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;T;.;T;.

Eigen

Benign

-0.077

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

D;D;D;D;D

MetaRNN

Benign

0.0064

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;.;N;.;.

PhyloP100

2.5

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.91

N;N;N;N;N

REVEL

Benign

0.050

Sift

Benign

0.030

D;D;D;D;D

Sift4G

Benign

0.26

T;T;T;T;T

Polyphen

0.0

B;B;.;.;.

Vest4

0.13

MVP

0.40

MPC

0.78

ClinPred

0.015

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.058

gMVP

0.21

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over