17-63918814-T-G

Variant names:

• chr17-63918814-T-G
• rs6172
• NM_000515.5:c.-38A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.334
• 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• isolated growth hormone deficiency type II

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 (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

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.-38A>C		5_prime_UTR	Exon 1 of 5	NP_000506.2
	GH1	NM_022559.4		c.-38A>C		5_prime_UTR	Exon 1 of 5	NP_072053.1
	GH1	NM_022560.4		c.-38A>C		5_prime_UTR	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.-38A>C		5_prime_UTR	Exon 1 of 5	ENSP00000312673.5
	GH1	ENST00000458650.6	TSL:1	c.-38A>C		5_prime_UTR	Exon 1 of 5	ENSP00000408486.2
	ENSG00000285947	ENST00000647774.1		c.287-308A>C		intron	N/A	ENSP00000497443.1

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3262 AN: 152060 Hom.: 42 Cov.: 32

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

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.: 35 AF XY: 0.0238 AC XY: 17274 AN XY: 726764

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: 81 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

GnomAD4 genome AF: 0.0215 AC: 3270 AN: 152178 Hom.: 42 Cov.: 32 AF XY: 0.0207 AC XY: 1541 AN XY: 74430

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: 12 AN: 5184

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4828

European-Finnish (FIN) AF: 0.0124 AC: 132 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0267 AC: 1818 AN: 67988

Other (OTH) AF: 0.0199 AC: 42 AN: 2110

Alfa AF: 0.0160 Hom.: 4

Bravo AF: 0.0229

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.7
DANN	Benign	0.56
PhyloP100		-0.33
PromoterAI		-0.0078	Neutral
Mutation Taster		=300/0	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: rs6172; hg19: chr17-61996174;