17-63917810-C-T

Variant names:

• chr17-63917810-C-T
• rs5388
• NM_000515.5:c.406G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000515.5(GH1):​c.406G>A​(p.Val136Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00762 in 1,614,182 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (44 hom.)
• Consequence: GH1 NM_000515.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.804
• Publications: 20 publications found

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]

GH1 Gene-Disease associations (from GenCC):

• isolated growth hormone deficiency type IA

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• isolated growth hormone deficiency type II

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• isolated growth hormone deficiency type IB

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short stature due to growth hormone qualitative anomaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285947 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028960973).
• BP6: Variant 17-63917810-C-T is Benign according to our data. Variant chr17-63917810-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197151.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00523 (797/152292) while in subpopulation NFE AF = 0.00876 (596/68032). AF 95% confidence interval is 0.00818. There are 3 homozygotes in GnomAd4. There are 335 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000515.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GH1	NM_000515.5	MANE Select	c.406G>A	p.Val136Ile	missense	Exon 4 of 5	NP_000506.2
	GH1	NM_022559.4		c.361G>A	p.Val121Ile	missense	Exon 4 of 5	NP_072053.1	B1A4G7
	GH1	NM_022560.4		c.286G>A	p.Val96Ile	missense	Exon 3 of 4	NP_072054.1	P01241-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GH1	ENST00000323322.10	TSL:1 MANE Select	c.406G>A	p.Val136Ile	missense	Exon 4 of 5	ENSP00000312673.5	P01241-1
	ENSG00000285947	ENST00000647774.1		c.682G>A	p.Val228Ile	missense	Exon 7 of 8	ENSP00000497443.1	A0A3B3ISS9
	GH1	ENST00000458650.6	TSL:1	c.361G>A	p.Val121Ile	missense	Exon 4 of 5	ENSP00000408486.2	P01241-2

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 796 AN: 152174 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00876

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00571 AC: 1436 AN: 251450 AF XY: 0.00540

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00743

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.00892

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00787 AC: 11506 AN: 1461890 Hom.: 44 Cov.: 35 AF XY: 0.00753 AC XY: 5478 AN XY: 727246

African (AFR) AF: 0.00152 AC: 51 AN: 33478

American (AMR) AF: 0.00698 AC: 312 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 79 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86256

European-Finnish (FIN) AF: 0.00335 AC: 179 AN: 53420

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00941 AC: 10467 AN: 1112012

Other (OTH) AF: 0.00634 AC: 383 AN: 60396

GnomAD4 genome AF: 0.00523 AC: 797 AN: 152292 Hom.: 3 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74464

African (AFR) AF: 0.00185 AC: 77 AN: 41570

American (AMR) AF: 0.00431 AC: 66 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00876 AC: 596 AN: 68032

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00758 Hom.: 8

Bravo AF: 0.00561

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0101 AC: 87

ExAC AF: 0.00545 AC: 662

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00895

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Decreased response to growth hormone stimulation test (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	10
DANN	Benign	0.68
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.39	N
PhyloP100		0.80
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.23
Sift	Benign	0.21	T
Sift4G	Benign	0.50	T
Polyphen		0.0020	B
Vest4		0.11
MVP		0.64
MPC		0.084
ClinPred		0.0042	T
GERP RS		2.9
Varity_R		0.12
gMVP		0.35
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs5388; hg19: chr17-61995170;