Genetic Variant NM_000515.5:c.456+90T>A (chr17-63917670-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000515.5(GH1):c.456+90T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,613,692 control chromosomes in the GnomAD database, including 125,177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 9221 hom., cov: 32)

Exomes 𝑓: 0.39 ( 115956 hom. )

Consequence

GH1
NM_000515.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.02

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 links:

ENSG00000285947 (HGNC:):

ENSG00000285947 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 17-63917670-A-T is Benign according to our data. Variant chr17-63917670-A-T is described in ClinVar as [Benign]. Clinvar id is 1293215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GH1	NM_000515.5 link	c.456+90T>A	intron_variant	Intron 4 of 4	ENST00000323322.10	NP_000506.2	P01241-1B1A4G6
GH1	NM_022559.4 link	c.411+90T>A	intron_variant	Intron 4 of 4		NP_072053.1	P01241-2B1A4G7
GH1	NM_022560.4 link	c.336+90T>A	intron_variant	Intron 3 of 3		NP_072054.1	P01241-5
LOC112268204	XR_002958148.2 link	n.388+26A>T	intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GH1	ENST00000323322.10 link	c.456+90T>A		intron_variant	Intron 4 of 4	1	NM_000515.5	ENSP00000312673.5		P01241-1
ENSG00000285947	ENST00000647774.1 link	c.732+90T>A		intron_variant	Intron 7 of 7			ENSP00000497443.1		A0A3B3ISS9

Frequencies

GnomAD3 genomes

AF:

0.322

AC:

48984

AN:

151980

Hom.:

9216

Cov.:

show subpopulations

Gnomad AFR

AF:

0.115

Gnomad AMI

AF:

0.525

Gnomad AMR

AF:

0.353

Gnomad ASJ

AF:

0.440

Gnomad EAS

AF:

0.410

Gnomad SAS

AF:

0.267

Gnomad FIN

AF:

0.409

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.415

Gnomad OTH

AF:

0.355

GnomAD4 exome

AF:

0.394

AC:

575572

AN:

1461594

Hom.:

115956

Cov.:

AF XY:

0.392

AC XY:

284997

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.103

Gnomad4 AMR exome

AF:

0.368

Gnomad4 ASJ exome

AF:

0.454

Gnomad4 EAS exome

AF:

0.413

Gnomad4 SAS exome

AF:

0.281

Gnomad4 FIN exome

AF:

0.399

Gnomad4 NFE exome

AF:

0.410

Gnomad4 OTH exome

AF:

0.391

GnomAD4 genome

AF:

0.322

AC:

49007

AN:

152098

Hom.:

9221

Cov.:

AF XY:

0.321

AC XY:

23881

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.115

Gnomad4 AMR

AF:

0.353

Gnomad4 ASJ

AF:

0.440

Gnomad4 EAS

AF:

0.410

Gnomad4 SAS

AF:

0.269

Gnomad4 FIN

AF:

0.409

Gnomad4 NFE

AF:

0.415

Gnomad4 OTH

AF:

0.358

Alfa

AF:

0.249

Hom.:

662

Bravo

AF:

0.314

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20650818, 10720078, 11904318) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.60

DANN

Benign

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over