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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003865.3. 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_003865.3	MANE Select	c.478C>T	p.Arg160Cys	missense	Exon 4 of 4	NP_003856.1
	HESX1	NM_001376058.1		c.478C>T	p.Arg160Cys	missense	Exon 7 of 7	NP_001362987.1
	HESX1	NM_001376059.1		c.478C>T	p.Arg160Cys	missense	Exon 6 of 6	NP_001362988.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HESX1	ENST00000295934.8	TSL:1 MANE Select	c.478C>T	p.Arg160Cys	missense	Exon 4 of 4	ENSP00000295934.3
	HESX1	ENST00000918124.1		c.499C>T	p.Arg167Cys	missense	Exon 4 of 4	ENSP00000588183.1
	HESX1	ENST00000647958.1		c.478C>T	p.Arg160Cys	missense	Exon 7 of 7	ENSP00000498190.1

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Septo-optic dysplasia sequence (1)
1	-	-	Septo-optic dysplasia sequence;C2750027:GROWTH HORMONE DEFICIENCY WITH PITUITARY ANOMALIES (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		5.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.97		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;