3-57211294-A-G

Variant names:

• chr3-57211294-A-G
• rs6774584
• NM_001376058.1:c.-111+41T>C

Variant summary

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

The NM_001376058.1(HESX1):​c.-111+41T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 150,688 control chromosomes in the GnomAD database, including 17,474 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 (17474 hom., cov: 27)
• Consequence: HESX1 NM_001376058.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.531
• Publications: 3 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376058.1. 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.-111+41T>C		intron	N/A	NP_001362987.1	Q9UBX0
	HESX1	NM_001376059.1		c.-110-11266T>C		intron	N/A	NP_001362988.1	Q9UBX0
	HESX1	NM_001376060.1		c.-110-11266T>C		intron	N/A	NP_001362989.1	Q9UBX0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HESX1	ENST00000647958.1		c.-111+41T>C		intron	N/A	ENSP00000498190.1	Q9UBX0
	HESX1	ENST00000495160.2	TSL:3	c.-110-11266T>C		intron	N/A	ENSP00000419615.2	J3KR67

Frequencies

GnomAD3 genomes AF: 0.471 AC: 70888 AN: 150578 Hom.: 17442 Cov.: 27

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.921

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.457

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

GnomAD4 genome AF: 0.471 AC: 70967 AN: 150688 Hom.: 17474 Cov.: 27 AF XY: 0.480 AC XY: 35264 AN XY: 73476

African (AFR) AF: 0.434 AC: 17776 AN: 40964

American (AMR) AF: 0.574 AC: 8674 AN: 15114

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1755 AN: 3466

East Asian (EAS) AF: 0.921 AC: 4682 AN: 5084

South Asian (SAS) AF: 0.538 AC: 2570 AN: 4776

European-Finnish (FIN) AF: 0.507 AC: 5154 AN: 10166

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.424 AC: 28730 AN: 67834

Other (OTH) AF: 0.463 AC: 964 AN: 2084

Alfa AF: 0.451 Hom.: 2059

Bravo AF: 0.475

Asia WGS AF: 0.714 AC: 2479 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.14
DANN	Benign	0.46
PhyloP100		-0.53

Splicing

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

Other links and lift over

dbSNP: rs6774584; hg19: chr3-57245322;