rs3806622

Positions:

• chr3-57226802-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001376061.1(HESX1):​c.-152+5G>C variant causes a splice donor 5th base, 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_donor_5th_base, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0490

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HESX1	XM_005265526.5	c.-617G>C		5_prime_UTR_variant	1/5		XP_005265583.1
HESX1	XM_047449142.1	c.-785G>C		5_prime_UTR_variant	1/6		XP_047305098.1
HESX1	NM_001376058.1	c.-319-466G>C		intron_variant			NP_001362987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HESX1	ENST00000647958.1	c.-319-466G>C		intron_variant				ENSP00000498190	P1

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

Gnomad4 AFR AF: 0.437

Gnomad4 AMR AF: 0.582

Gnomad4 ASJ AF: 0.507

Gnomad4 EAS AF: 0.849

Gnomad4 SAS AF: 0.542

Gnomad4 FIN AF: 0.516

Gnomad4 NFE AF: 0.425

Gnomad4 OTH AF: 0.470

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.2
DANN	Benign	0.52

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3806622; hg19: chr3-57260830;