17-63917375-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000515.5(GH1):c.588G>A(p.Met196Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GH1 NM_000515.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65

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]

LOC112268204 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GH1	NM_000515.5	c.588G>A	p.Met196Ile	missense_variant	5/5	ENST00000323322.10
LOC112268204	XR_002958148.2	n.341-222C>T		intron_variant, non_coding_transcript_variant
GH1	NM_022559.4	c.543G>A	p.Met181Ile	missense_variant	5/5
GH1	NM_022560.4	c.468G>A	p.Met156Ile	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GH1	ENST00000323322.10	c.588G>A	p.Met196Ile	missense_variant	5/5	1	NM_000515.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461690 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ateleiotic dwarfism Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 24, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	0.0086	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.85	T;T;T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationTaster	Benign	1.0	D;D;D;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.5	D;D;D;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.020	D;D;D;D
Sift4G	Benign	0.071	T;T;T;T
Polyphen		0.021, 0.083	.;.;B;B
Vest4		0.27
MutPred		0.77		.;.;Gain of ubiquitination at K198 (P = 0.095);.;
MVP		0.89
MPC		0.16
ClinPred		0.97	D
GERP RS		2.6
Varity_R		0.53
gMVP		0.42

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: rs1907385621; hg19: chr17-61994735; COSMIC: COSV60111615; COSMIC: COSV60111615;