rs2001345

Variant names:

• chr17-63918770-T-C
• rs2001345
• NM_000515.5:c.7A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-63918770-T-C
• chr17-63918770-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000515.5(GH1):​c.7A>G​(p.Thr3Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,607,952 control chromosomes in the GnomAD database, including 537 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.035 (222 hom., cov: 32)
  • Exomes 𝑓: 0.012 (315 hom.)
• Consequence: GH1 NM_000515.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.06
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017983615).
• BP6: Variant 17-63918770-T-C is Benign according to our data. Variant chr17-63918770-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 289503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0926 is higher than 0.05.

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.7A>G	p.Thr3Ala	missense	Exon 1 of 5	NP_000506.2
	GH1	NM_022559.4		c.7A>G	p.Thr3Ala	missense	Exon 1 of 5	NP_072053.1
	GH1	NM_022560.4		c.7A>G	p.Thr3Ala	missense	Exon 1 of 4	NP_072054.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GH1	ENST00000323322.10	TSL:1 MANE Select	c.7A>G	p.Thr3Ala	missense	Exon 1 of 5	ENSP00000312673.5
	GH1	ENST00000458650.6	TSL:1	c.7A>G	p.Thr3Ala	missense	Exon 1 of 5	ENSP00000408486.2
	ENSG00000285947	ENST00000647774.1		c.287-264A>G		intron	N/A	ENSP00000497443.1

Frequencies

GnomAD3 genomes AF: 0.0352 AC: 5353 AN: 152126 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.0952

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.0319

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.0143 AC: 3583 AN: 249884 AF XY: 0.0130

Gnomad AFR exome AF: 0.0829

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.00918

Gnomad EAS exome AF: 0.0271

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00919

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0118 AC: 17209 AN: 1455708 Hom.: 315 Cov.: 35 AF XY: 0.0115 AC XY: 8325 AN XY: 724374

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0853 AC: 2754 AN: 32288

American (AMR) AF: 0.0123 AC: 548 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00989 AC: 258 AN: 26078

East Asian (EAS) AF: 0.0297 AC: 1179 AN: 39692

South Asian (SAS) AF: 0.00625 AC: 539 AN: 86174

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53418

Middle Eastern (MID) AF: 0.0229 AC: 131 AN: 5728

European-Non Finnish (NFE) AF: 0.00979 AC: 10841 AN: 1107614

Other (OTH) AF: 0.0144 AC: 866 AN: 60104

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0352 AC: 5356 AN: 152244 Hom.: 222 Cov.: 32 AF XY: 0.0343 AC XY: 2552 AN XY: 74454

African (AFR) AF: 0.0950 AC: 3944 AN: 41502

American (AMR) AF: 0.0188 AC: 288 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3468

East Asian (EAS) AF: 0.0320 AC: 166 AN: 5186

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4832

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10626

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0118 AC: 803 AN: 68008

Other (OTH) AF: 0.0246 AC: 52 AN: 2116

Alfa AF: 0.00745 Hom.: 1

Bravo AF: 0.0392

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.0765 AC: 337

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.0184 AC: 2230

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Decreased response to growth hormone stimulation test (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.035
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.11
DANN	Benign	0.13
DEOGEN2	Benign	0.069	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-1.6	N
PhyloP100		-1.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.27
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.036
MPC		0.10
ClinPred		0.00032	T
GERP RS		-0.16
PromoterAI		0.0080	Neutral
Varity_R		0.036
gMVP		0.21
Mutation Taster		=99/1	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: rs2001345; hg19: chr17-61996130;