rs863223307

Variant names:

• chr17-63918012-C-T
• rs863223307
• NM_000515.5:c.291+5G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000515.5(GH1):​c.291+5G>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GH1 NM_000515.5 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.28

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-63918012-C-T is Pathogenic according to our data. Variant chr17-63918012-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15975.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GH1	NM_000515.5	c.291+5G>A		splice_region_variant, intron_variant	Intron 3 of 4	ENST00000323322.10	NP_000506.2
GH1	NM_022559.4	c.246+5G>A		splice_region_variant, intron_variant	Intron 3 of 4		NP_072053.1
GH1	NM_022560.4	c.172-88G>A		intron_variant	Intron 2 of 3		NP_072054.1
LOC112268204	XR_002958148.2	n.*86C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GH1	ENST00000323322.10	c.291+5G>A		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_000515.5	ENSP00000312673.5
ENSG00000285947	ENST00000647774.1	c.567+5G>A		splice_region_variant, intron_variant	Intron 6 of 7			ENSP00000497443.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Idiopathic growth hormone deficiency Pathogenic:1

Jul 31, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GH1 c.291+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. Multiple publication reports experimental evidence that this variant affects mRNA splicing, resulting in exon 3 skipping, confirmed in vivo and in vitro evidenced by shortened mRNA transcript length and cDNA sequencing products with absent exon 3 (e.g. Missarelli_HumGen_1997, Moseley_2002). The variant was absent in 251464 control chromosomes. c.291+5G>A has been reported in the literature in multiple heterozygous individuals affected with Autosomal Dominant Idiopathic Growth Hormone Deficiency, additionally showing segregation with disease in multiple families (e.g. Missarelli_HumGen_1997, Moseley_2002). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9385381, 11836331). ClinVar contains an entry for this variant (Variation ID: 15975). Based on the evidence outlined above, the variant was classified as pathogenic. -

Autosomal dominant isolated somatotropin deficiency Pathogenic:1

Sep 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.90		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs863223307; hg19: chr17-61995372;