chr3-57226802-C-G

Variant names:

• chr3-57226802-C-G
• rs3806622
• XM_005265526.5:c.-617G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001376061.1(HESX1):​c.-152+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 151,882 control chromosomes in the GnomAD database, including 17,488 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (17488 hom., cov: 32)
• Consequence: HESX1 NM_001376061.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0490
• Publications: 5 publications found

Genes affected

HESX1 (HGNC:4877): (HESX homeobox 1) This gene encodes a conserved homeobox protein that is a transcriptional repressor in the developing forebrain and pituitary gland. Mutations in this gene are associated with septooptic dysplasia, HESX1-related growth hormone deficiency, and combined pituitary hormone deficiency. [provided by RefSeq, Jul 2008]

HESX1 Gene-Disease associations (from GenCC):

• septooptic dysplasia

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• combined pituitary hormone deficiencies, genetic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypothyroidism due to deficient transcription factors involved in pituitary development or function

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary stalk interruption syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376061.1. 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
	HESX1	NM_001376058.1		c.-319-466G>C		intron	N/A	NP_001362987.1
	HESX1	NM_001376059.1		c.-151-466G>C		intron	N/A	NP_001362988.1
	HESX1	NM_001376060.1		c.-151-466G>C		intron	N/A	NP_001362989.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HESX1	ENST00000647958.1		c.-319-466G>C		intron	N/A	ENSP00000498190.1

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71575 AN: 151764 Hom.: 17451 Cov.: 32

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.849

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.464

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.472 AC: 71664 AN: 151882 Hom.: 17488 Cov.: 32 AF XY: 0.481 AC XY: 35706 AN XY: 74210

African (AFR) AF: 0.437 AC: 18099 AN: 41410

American (AMR) AF: 0.582 AC: 8880 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1758 AN: 3470

East Asian (EAS) AF: 0.849 AC: 4376 AN: 5152

South Asian (SAS) AF: 0.542 AC: 2604 AN: 4808

European-Finnish (FIN) AF: 0.516 AC: 5441 AN: 10536

Middle Eastern (MID) AF: 0.462 AC: 135 AN: 292

European-Non Finnish (NFE) AF: 0.425 AC: 28891 AN: 67932

Other (OTH) AF: 0.470 AC: 992 AN: 2112

Alfa AF: 0.448 Hom.: 2060

Bravo AF: 0.474

Asia WGS AF: 0.687 AC: 2386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.2
DANN	Benign	0.52
PhyloP100		0.049
PromoterAI		-0.056	Neutral

Splicing

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

Other links and lift over

dbSNP: rs3806622; hg19: chr3-57260830;