17-63918814-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000515.5(GH1):c.-38A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,613,064 control chromosomes in the GnomAD database, including 548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 42 hom., cov: 32)

Exomes 𝑓: 0.024 ( 506 hom. )

Consequence

GH1
NM_000515.5 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.334

Publications

10 publications found

Variant links:

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

GH1 links:

ENSG00000285947 (HGNC:):

ENSG00000285947 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 17-63918814-T-G is Benign according to our data. Variant chr17-63918814-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 891384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0215 (3270/152178) while in subpopulation NFE AF = 0.0267 (1818/67988). AF 95% confidence interval is 0.0257. There are 42 homozygotes in GnomAd4. There are 1541 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
GH1	NM_000515.5 link	c.-38A>C	5_prime_UTR_variant	Exon 1 of 5	ENST00000323322.10	NP_000506.2
GH1	NM_022559.4 link	c.-38A>C	5_prime_UTR_variant	Exon 1 of 5		NP_072053.1
GH1	NM_022560.4 link	c.-38A>C	5_prime_UTR_variant	Exon 1 of 4		NP_072054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GH1	ENST00000323322.10 link	c.-38A>C		5_prime_UTR_variant	Exon 1 of 5	1	NM_000515.5	ENSP00000312673.5
ENSG00000285947	ENST00000647774.1 link	c.287-308A>C		intron_variant	Intron 4 of 7			ENSP00000497443.1

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

3262

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0153

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0229

Gnomad ASJ

AF:

0.0450

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0157

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0267

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0197

AC:

4953

AN:

250918

AF XY:

0.0199

show subpopulations

Gnomad AFR exome

AF:

0.0125

Gnomad AMR exome

AF:

0.0207

Gnomad ASJ exome

AF:

0.0377

Gnomad EAS exome

AF:

0.00256

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.0245

Gnomad OTH exome

AF:

0.0229

GnomAD4 exome

AF:

0.0240

AC:

35033

AN:

1460886

Hom.:

506

Cov.:

AF XY:

0.0238

AC XY:

17274

AN XY:

726764

show subpopulations

African (AFR)

AF:

0.0136

AC:

456

AN:

33424

American (AMR)

AF:

0.0208

AC:

932

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0413

AC:

1078

AN:

26130

East Asian (EAS)

AF:

0.00204

AC:

AN:

39700

South Asian (SAS)

AF:

0.0155

AC:

1340

AN:

86200

European-Finnish (FIN)

AF:

0.0124

AC:

662

AN:

53420

Middle Eastern (MID)

AF:

0.0224

AC:

129

AN:

5756

European-Non Finnish (NFE)

AF:

0.0260

AC:

28946

AN:

1111208

Other (OTH)

AF:

0.0233

AC:

1409

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

1818

3637

5455

7274

9092

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1088

2176

3264

4352

5440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0215

AC:

3270

AN:

152178

Hom.:

Cov.:

AF XY:

0.0207

AC XY:

1541

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0154

AC:

640

AN:

41492

American (AMR)

AF:

0.0228

AC:

348

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0450

AC:

156

AN:

3468

East Asian (EAS)

AF:

0.00231

AC:

AN:

5184

South Asian (SAS)

AF:

0.0162

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0124

AC:

132

AN:

10626

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0267

AC:

1818

AN:

67988

Other (OTH)

AF:

0.0199

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

163

326

489

652

815

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0160

Hom.:

Bravo

AF:

0.0229

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 19, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria.

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Decreased response to growth hormone stimulation test

Benign:1

Jan 18, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.7

(source)

DANN

Benign

0.56

PhyloP100

-0.33

PromoterAI

-0.0078

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over