rs137853219

Positions:

• chr17-63918458-C-A
• chr17-63918458-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000515.5(GH1):​c.59G>T​(p.Trp20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 1.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GH1	NM_000515.5	c.59G>T	p.Trp20Leu	missense_variant	2/5	ENST00000323322.10
GH1	NM_022559.4	c.59G>T	p.Trp20Leu	missense_variant	2/5
GH1	NM_022560.4	c.59G>T	p.Trp20Leu	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GH1	ENST00000323322.10	c.59G>T	p.Trp20Leu	missense_variant	2/5	1	NM_000515.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.84	.;.;D;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.1	M;M;M;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.8	D;D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.020	D;D;T;D
Sift4G	Benign	0.079	T;T;T;D
Polyphen		0.97, 0.027	.;.;D;B
Vest4		0.47
MutPred		0.62		Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);
MVP		0.92
MPC		0.57
ClinPred		0.90	D
GERP RS		1.9
Varity_R		0.41
gMVP		0.51

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: rs137853219; hg19: chr17-61995818;