chr17-63917338-G-C

Variant names:

• chr17-63917338-G-C
• rs755905735
• NM_000515.5:c.625C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000515.5(GH1):​c.625C>G​(p.Arg209Gly) 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GH1 NM_000515.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.52

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]

ENSG00000285947 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GH1	NM_000515.5	c.625C>G	p.Arg209Gly	missense_variant	Exon 5 of 5	ENST00000323322.10	NP_000506.2
GH1	NM_022559.4	c.580C>G	p.Arg194Gly	missense_variant	Exon 5 of 5		NP_072053.1
GH1	NM_022560.4	c.505C>G	p.Arg169Gly	missense_variant	Exon 4 of 4		NP_072054.1
LOC112268204	XR_002958148.2	n.341-259G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GH1	ENST00000323322.10	c.625C>G	p.Arg209Gly	missense_variant	Exon 5 of 5	1	NM_000515.5	ENSP00000312673.5
ENSG00000285947	ENST00000647774.1	c.901C>G	p.Arg301Gly	missense_variant	Exon 8 of 8			ENSP00000497443.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;.;D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.7	.;.;H;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.6	D;D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.99, 0.99	.;.;D;D
Vest4		0.94
MutPred		0.92		.;.;Gain of glycosylation at S214 (P = 0.0893);.;
MVP		0.98
MPC		0.51
ClinPred		0.96	D
GERP RS		2.6
Varity_R		0.91
gMVP		0.78

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: rs755905735; hg19: chr17-61994698;