chr14-61738090-C-T

Position:

• chr14-61738090-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 13/20 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.51

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

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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/exons	MANE	UniProt
HIF1A	NM_001530.4	c.1253C>T	p.Thr418Ile	missense_variant	10/15	ENST00000337138.9
HIF1A-AS3	NR_144368.1	n.213+12795G>A		intron_variant, non_coding_transcript_variant
HIF1A	NM_001243084.2	c.1325C>T	p.Thr442Ile	missense_variant	10/15
HIF1A	NM_181054.3	c.1253C>T	p.Thr418Ile	missense_variant	10/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HIF1A	ENST00000337138.9	c.1253C>T	p.Thr418Ile	missense_variant	10/15	1	NM_001530.4	P4
HIF1A-AS3	ENST00000660325.2	n.215+12795G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 617 AN: 151686 Hom.: 1 Cov.: 32

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

GnomAD3 exomes AF: 0.00384 AC: 897 AN: 233808 Hom.: 5 AF XY: 0.00391 AC XY: 495 AN XY: 126534

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 SAS exome AF: 0.000368

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.: 38 Cov.: 32 AF XY: 0.00569 AC XY: 4073 AN XY: 715374

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00485

Gnomad4 ASJ exome AF: 0.00169

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000458

Gnomad4 FIN exome AF: 0.000721

Gnomad4 NFE exome AF: 0.00694

Gnomad4 OTH exome AF: 0.00544

GnomAD4 genome AF: 0.00406 AC: 617 AN: 151792 Hom.: 1 Cov.: 32 AF XY: 0.00375 AC XY: 278 AN XY: 74160

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00721

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.000574

Gnomad4 NFE AF: 0.00584

Gnomad4 OTH AF: 0.00996

Alfa AF: 0.00556 Hom.: 4

Bravo AF: 0.00451

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00358 AC: 435

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 07, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
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	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
MetaRNN	Benign	0.0064	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;N;.;.
MutationTaster	Benign	0.94	D;D;D;D;D
PrimateAI	Benign	0.42	T
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	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.058
gMVP		0.21

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

Other links and lift over

dbSNP: rs41508050; hg19: chr14-62204808;