rs3744287

Variant names:

• chr17-63918558-A-G
• rs3744287
• NM_000515.5:c.11-52T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000515.5(GH1):​c.11-52T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,611,770 control chromosomes in the GnomAD database, including 277 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.017 (36 hom., cov: 32)
  • Exomes 𝑓: 0.013 (241 hom.)
• Consequence: GH1 NM_000515.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 3 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), Ambry Genetics, Orphanet
• 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 -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GH1	NM_000515.5	c.11-52T>C		intron_variant	Intron 1 of 4	ENST00000323322.10	NP_000506.2
GH1	NM_022559.4	c.11-52T>C		intron_variant	Intron 1 of 4		NP_072053.1
GH1	NM_022560.4	c.11-52T>C		intron_variant	Intron 1 of 3		NP_072054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GH1	ENST00000323322.10	c.11-52T>C		intron_variant	Intron 1 of 4	1	NM_000515.5	ENSP00000312673.5
ENSG00000285947	ENST00000647774.1	c.287-52T>C		intron_variant	Intron 4 of 7			ENSP00000497443.1

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2557 AN: 151412 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.0523

Gnomad EAS AF: 0.0774

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.00200

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0184 AC: 4607 AN: 249758 AF XY: 0.0183

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.0441

Gnomad EAS exome AF: 0.0812

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.0211

GnomAD4 exome AF: 0.0134 AC: 19561 AN: 1460242 Hom.: 241 Cov.: 34 AF XY: 0.0135 AC XY: 9804 AN XY: 726428

African (AFR) AF: 0.0228 AC: 763 AN: 33434

American (AMR) AF: 0.0120 AC: 536 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0433 AC: 1132 AN: 26136

East Asian (EAS) AF: 0.0615 AC: 2441 AN: 39698

South Asian (SAS) AF: 0.0223 AC: 1921 AN: 86200

European-Finnish (FIN) AF: 0.00131 AC: 70 AN: 53390

Middle Eastern (MID) AF: 0.0211 AC: 101 AN: 4790

European-Non Finnish (NFE) AF: 0.0104 AC: 11533 AN: 1111660

Other (OTH) AF: 0.0177 AC: 1064 AN: 60244

GnomAD4 genome AF: 0.0169 AC: 2562 AN: 151528 Hom.: 36 Cov.: 32 AF XY: 0.0176 AC XY: 1300 AN XY: 73992

African (AFR) AF: 0.0222 AC: 917 AN: 41230

American (AMR) AF: 0.0142 AC: 216 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.0523 AC: 181 AN: 3462

East Asian (EAS) AF: 0.0774 AC: 398 AN: 5142

South Asian (SAS) AF: 0.0194 AC: 93 AN: 4788

European-Finnish (FIN) AF: 0.00200 AC: 21 AN: 10516

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0100 AC: 679 AN: 67868

Other (OTH) AF: 0.0256 AC: 54 AN: 2108

Alfa AF: 0.0162 Hom.: 7

Bravo AF: 0.0178

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.24
PhyloP100		-1.5
BranchPoint Hunter		0.0
PromoterAI		0.0060	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3744287; hg19: chr17-61995918;