14-61738090-C-T

Variant names:

• chr14-61738090-C-T
• rs41508050
• NM_001530.4:c.1253C>T

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.51
• Publications: 33 publications found

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]

ENSG00000258667 (HGNC:):

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

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001530.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIF1A	NM_001530.4	MANE Select	c.1253C>T	p.Thr418Ile	missense	Exon 10 of 15	NP_001521.1	D0VY79
	HIF1A	NM_001243084.2		c.1325C>T	p.Thr442Ile	missense	Exon 10 of 15	NP_001230013.1	Q16665-3
	HIF1A	NM_181054.3		c.1253C>T	p.Thr418Ile	missense	Exon 10 of 14	NP_851397.1	Q16665-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HIF1A	ENST00000337138.9	TSL:1 MANE Select	c.1253C>T	p.Thr418Ile	missense	Exon 10 of 15	ENSP00000338018.4	Q16665-1
	HIF1A	ENST00000539097.2	TSL:1	c.1325C>T	p.Thr442Ile	missense	Exon 10 of 15	ENSP00000437955.1	Q16665-3
	HIF1A	ENST00000394997.5	TSL:1	c.1256C>T	p.Thr419Ile	missense	Exon 10 of 15	ENSP00000378446.1	A8MYV6

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

GnomAD2 exomes AF: 0.00384 AC: 897 AN: 233808 AF XY: 0.00391

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

African (AFR) AF: 0.00105 AC: 34 AN: 32464

American (AMR) AF: 0.00485 AC: 198 AN: 40816

Ashkenazi Jewish (ASJ) AF: 0.00169 AC: 42 AN: 24800

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.000458 AC: 38 AN: 82918

European-Finnish (FIN) AF: 0.000721 AC: 38 AN: 52740

Middle Eastern (MID) AF: 0.00727 AC: 41 AN: 5642

European-Non Finnish (NFE) AF: 0.00694 AC: 7652 AN: 1102112

Other (OTH) AF: 0.00544 AC: 323 AN: 59366

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

African (AFR) AF: 0.00147 AC: 61 AN: 41394

American (AMR) AF: 0.00721 AC: 110 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4804

European-Finnish (FIN) AF: 0.000574 AC: 6 AN: 10450

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00584 AC: 397 AN: 67936

Other (OTH) AF: 0.00996 AC: 21 AN: 2108

Alfa AF: 0.00541 Hom.: 11

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.077
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.050
Sift	Benign	0.030	D
Sift4G	Benign	0.26	T
Polyphen		0.0	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
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs41508050; hg19: chr14-62204808;