rs141063672

chr3-57198230-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_003865.3(HESX1):c.525G>A(p.Ala175=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,611,574 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: HESX1 NM_003865.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -1.93

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 3-57198230-C-T is Benign according to our data. Variant chr3-57198230-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197222.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}. Variant chr3-57198230-C-T is described in Lovd as [Benign]. Variant chr3-57198230-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00118 (180/152026) while in subpopulation NFE AF= 0.00212 (144/67958). AF 95% confidence interval is 0.00184. There are 0 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HESX1	NM_003865.3	c.525G>A	p.Ala175=	synonymous_variant	4/4	ENST00000295934.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HESX1	ENST00000295934.8	c.525G>A	p.Ala175=	synonymous_variant	4/4	1	NM_003865.3	P1
HESX1	ENST00000647958.1	c.525G>A	p.Ala175=	synonymous_variant	7/7			P1
HESX1	ENST00000473921.2	c.423G>A	p.Ala141=	synonymous_variant	3/3	5

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 151908 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000993 AC: 249 AN: 250672 Hom.: 2 AF XY: 0.00108 AC XY: 147 AN XY: 135550

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00178 AC: 2598 AN: 1459548 Hom.: 2 Cov.: 30 AF XY: 0.00179 AC XY: 1300 AN XY: 726088

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152026 Hom.: 0 Cov.: 32 AF XY: 0.000982 AC XY: 73 AN XY: 74318

Gnomad4 AFR AF: 0.000434

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000951

Gnomad4 NFE AF: 0.00212

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00120

EpiCase AF: 0.00224

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	HESX1: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 08, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 05, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Septo-optic dysplasia sequence Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Septo-optic dysplasia sequence;C2750027:Growth hormone deficiency with pituitary anomalies Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	5.0
Dann	Benign	0.56

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: rs141063672; hg19: chr3-57232258;