rs28936702

Variant names:

• chr3-57198277-G-A
• rs28936702
• NM_003865.3:c.478C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-57198277-G-A
• chr3-57198277-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM5 PP3_Strong PP5_Moderate

The NM_003865.3(HESX1):​c.478C>T​(p.Arg160Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000185 in 1,460,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R160H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: HESX1 NM_003865.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.82
• Publications: 15 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a helix (size 15) in uniprot entity HESX1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003865.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-57198276-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 985575.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 3-57198277-G-A is Pathogenic according to our data. Variant chr3-57198277-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7691.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HESX1	NM_003865.3	c.478C>T	p.Arg160Cys	missense_variant	Exon 4 of 4	ENST00000295934.8	NP_003856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HESX1	ENST00000295934.8	c.478C>T	p.Arg160Cys	missense_variant	Exon 4 of 4	1	NM_003865.3	ENSP00000295934.3
HESX1	ENST00000647958.1	c.478C>T	p.Arg160Cys	missense_variant	Exon 7 of 7			ENSP00000498190.1
HESX1	ENST00000473921.2	c.376C>T	p.Arg126Cys	missense_variant	Exon 3 of 3	5		ENSP00000418918.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250912 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1460524 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 726566

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111094

Other (OTH) AF: 0.0000166 AC: 1 AN: 60322

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000911 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Septo-optic dysplasia sequence;C2750027:GROWTH HORMONE DEFICIENCY WITH PITUITARY ANOMALIES Pathogenic:1

May 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 160 of the HESX1 protein (p.Arg160Cys). This variant is present in population databases (rs28936702, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive septo-optic dysplasia (PMID: 9620767, 25500790, 27000987, 33098107). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg53Cys. ClinVar contains an entry for this variant (Variation ID: 7691). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HESX1 function (PMID: 9620767, 11748154, 19093031, 25910213). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Septo-optic dysplasia sequence Pathogenic:1

Jun 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.1	H;H;.
PhyloP100		5.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.5	.;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	D;D;.
Vest4		0.81, 0.75
MutPred		0.97		Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);.;
MVP		1.0
MPC		0.41
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.91
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28936702; hg19: chr3-57232305;