17-63918072-C-A

Variant names:

• chr17-63918072-C-A
• rs137853222
• NM_000515.5:c.236G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000515.5(GH1):​c.236G>T​(p.Cys79Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C79S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GH1 NM_000515.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.18
• Publications: 5 publications found

Genes affected

GH1 (HGNC:4261): (growth hormone 1) The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. The five genes share a remarkably high degree of sequence identity. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed in the pituitary but not in placental tissue as is the case for the other four genes in the growth hormone locus. Mutations in or deletions of the gene lead to growth hormone deficiency and short stature. [provided by RefSeq, Jul 2008]

GH1 Gene-Disease associations (from GenCC):

• isolated growth hormone deficiency type IA

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• isolated growth hormone deficiency type II

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• isolated growth hormone deficiency type IB

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short stature due to growth hormone qualitative anomaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285947 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000515.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-63918072-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 15981.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000515.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GH1	NM_000515.5	MANE Select	c.236G>T	p.Cys79Phe	missense	Exon 3 of 5	NP_000506.2
	GH1	NM_022559.4		c.191G>T	p.Cys64Phe	missense	Exon 3 of 5	NP_072053.1
	GH1	NM_022560.4		c.172-148G>T		intron	N/A	NP_072054.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GH1	ENST00000323322.10	TSL:1 MANE Select	c.236G>T	p.Cys79Phe	missense	Exon 3 of 5	ENSP00000312673.5
	ENSG00000285947	ENST00000647774.1		c.512G>T	p.Cys171Phe	missense	Exon 6 of 8	ENSP00000497443.1
	GH1	ENST00000458650.6	TSL:1	c.191G>T	p.Cys64Phe	missense	Exon 3 of 5	ENSP00000408486.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		4.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.86
MVP		0.98
MPC		0.25
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.97
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -9

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

Other links and lift over

dbSNP: rs137853222; hg19: chr17-61995432;