17-63918016-C-T

Position:

• chr17-63918016-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000515.5(GH1):​c.291+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GH1 NM_000515.5 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.29

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.18195719 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-63918016-C-T is Pathogenic according to our data. Variant chr17-63918016-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63918016-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GH1	NM_000515.5	c.291+1G>A		splice_donor_variant		ENST00000323322.10	NP_000506.2
GH1	NM_022559.4	c.246+1G>A		splice_donor_variant			NP_072053.1
GH1	NM_022560.4	c.172-92G>A		intron_variant			NP_072054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GH1	ENST00000323322.10	c.291+1G>A		splice_donor_variant		1	NM_000515.5	ENSP00000312673	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2019	Published functional studies demonstrate a damaging effect (skipping of exon 3 and loss of amino acid codons 32-71, resulting in decreased cell viability and increased expression of stress response pathways leading to cell apoptosis) (Cogan et al., 1995; Ariyasu et al., 2013); Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24280736, 10445339, 8530604, 22139958, 18785993, 12720086, 10372722, 25525159, 19837935, 23736291) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 12, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 8530604). ClinVar contains an entry for this variant (Variation ID: 15970). Disruption of this splice site has been observed in individual(s) with autosomal dominant growth hormone deficiency (PMID: 8530604, 34850017). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 3 of the GH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. -

Autosomal dominant isolated somatotropin deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1999	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2024

The c.291+1G>A intronic alteration consists of a G to A substitution one nucleotide after exon 3 of the GH1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The exact functional effect of the altered amino acid sequence is unknown. Based on the supporting evidence, this alteration is pathogenic for isolated growth hormone deficiency type II (AD); however, the association of this alteration with isolated growth hormone deficiency type I (AR) is unknown. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in multiple individuals with isolated growth hormone deficiency type II (AD), including multiple cases of reported de novo occurrence (Halfmeyer, 2022; Saitoh, 1999; Cogan, 1995; Li, 2022; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Autosomal dominant isolated somatotropin deficiency;C0342573:Ateleiotic dwarfism;C1849779:Short stature due to growth hormone qualitative anomaly;C2748571:Isolated growth hormone deficiency type IB Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Benign	0.96
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs71640277; hg19: chr17-61995376;