rs740336

Variant names:

• chr7-30972062-C-T
• rs740336
• ENST00000409316.5:c.17C>T

Variant summary

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

The ENST00000409316.5(GHRHR):​c.17C>T​(p.Thr6Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,613,980 control chromosomes in the GnomAD database, including 1,264 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (322 hom., cov: 32)
  • Exomes 𝑓: 0.027 (942 hom.)
• Consequence: GHRHR ENST00000409316.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.82
• Publications: 8 publications found

Genes affected

GHRHR (HGNC:4266): (growth hormone releasing hormone receptor) This gene encodes a receptor for growth hormone-releasing hormone. Binding of this hormone to the receptor leads to synthesis and release of growth hormone. Mutations in this gene have been associated with isolated growth hormone deficiency (IGHD), also known as Dwarfism of Sindh, a disorder characterized by short stature. [provided by RefSeq, Jun 2010]

GHRHR Gene-Disease associations (from GenCC):

• isolated growth hormone deficiency type IB

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• isolated growth hormone deficiency, type 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016007125).
• BP6: Variant 7-30972062-C-T is Benign according to our data. Variant chr7-30972062-C-T is described in ClinVar as Benign. ClinVar VariationId is 36276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000409316.5. 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
	GHRHR	NM_000823.4	MANE Select	c.564C>T	p.His188His	synonymous	Exon 6 of 13	NP_000814.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRHR	ENST00000409316.5	TSL:1	c.17C>T	p.Thr6Ile	missense	Exon 4 of 10	ENSP00000386602.1
	GHRHR	ENST00000326139.7	TSL:1 MANE Select	c.564C>T	p.His188His	synonymous	Exon 6 of 13	ENSP00000320180.2
	GHRHR	ENST00000409904.7	TSL:1	c.372C>T	p.His124His	synonymous	Exon 3 of 10	ENSP00000387113.3

Frequencies

GnomAD3 genomes AF: 0.0473 AC: 7193 AN: 152130 Hom.: 320 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00579

Gnomad SAS AF: 0.0767

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0312 AC: 7839 AN: 251420 AF XY: 0.0332

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.00767

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.0225

Gnomad OTH exome AF: 0.0271

GnomAD4 exome AF: 0.0269 AC: 39322 AN: 1461732 Hom.: 942 Cov.: 32 AF XY: 0.0284 AC XY: 20652 AN XY: 727170

African (AFR) AF: 0.125 AC: 4186 AN: 33478

American (AMR) AF: 0.0136 AC: 607 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0174 AC: 454 AN: 26136

East Asian (EAS) AF: 0.00333 AC: 132 AN: 39698

South Asian (SAS) AF: 0.0789 AC: 6809 AN: 86254

European-Finnish (FIN) AF: 0.00337 AC: 180 AN: 53376

Middle Eastern (MID) AF: 0.0414 AC: 239 AN: 5766

European-Non Finnish (NFE) AF: 0.0224 AC: 24859 AN: 1111912

Other (OTH) AF: 0.0307 AC: 1856 AN: 60388

GnomAD4 genome AF: 0.0474 AC: 7213 AN: 152248 Hom.: 322 Cov.: 32 AF XY: 0.0468 AC XY: 3484 AN XY: 74444

African (AFR) AF: 0.117 AC: 4845 AN: 41516

American (AMR) AF: 0.0191 AC: 292 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.00580 AC: 30 AN: 5168

South Asian (SAS) AF: 0.0774 AC: 373 AN: 4820

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10626

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0221 AC: 1506 AN: 68026

Other (OTH) AF: 0.0397 AC: 84 AN: 2114

Alfa AF: 0.0302 Hom.: 410

Bravo AF: 0.0507

TwinsUK AF: 0.0221 AC: 82

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.111 AC: 487

ESP6500EA AF: 0.0222 AC: 191

ExAC AF: 0.0343 AC: 4169

Asia WGS AF: 0.0450 AC: 156 AN: 3478

EpiCase AF: 0.0242

EpiControl AF: 0.0268

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Idiopathic growth hormone deficiency (1)
-	-	1	Isolated growth hormone deficiency type IB (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.33
DANN	Benign	0.24
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.8
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.020
Polyphen		0.23	B
Vest4		0.24
ClinPred		0.011	T
GERP RS		-6.8
PromoterAI		-0.053	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs740336; hg19: chr7-31011677;