rs28936702

chr3-57198277-G-Achr3-57198277-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM5 PP3_Strong PP5

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 (no stars). 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 no assertion criteria provided P:1
• Conservation: PhyloP100: 5.82

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 15) in uniprot entity HESX1_HUMAN there are 7 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 id is 985575.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.
• 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 id is 7691.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-57198277-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-57198277-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HESX1	NM_003865.3	c.478C>T	p.Arg160Cys	missense_variant	4/4	ENST00000295934.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HESX1	ENST00000295934.8	c.478C>T	p.Arg160Cys	missense_variant	4/4	1	NM_003865.3	P1
HESX1	ENST00000647958.1	c.478C>T	p.Arg160Cys	missense_variant	7/7			P1
HESX1	ENST00000473921.2	c.376C>T	p.Arg126Cys	missense_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250912 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135754

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000307 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Septo-optic dysplasia sequence Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1998

- -

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
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.1	H;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.71	T
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs28936702; hg19: chr3-57232305;