7-30964121-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000823.4(GHRHR):c.53C>T(p.Pro18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,548,698 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: GHRHR NM_000823.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.263

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050522536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHRHR	NM_000823.4	c.53C>T	p.Pro18Leu	missense_variant	1/13	ENST00000326139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHRHR	ENST00000326139.7	c.53C>T	p.Pro18Leu	missense_variant	1/13	1	NM_000823.4	P1
GHRHR	ENST00000466427.1	n.285-4713C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000182 AC: 28 AN: 153766 Hom.: 0 AF XY: 0.000173 AC XY: 14 AN XY: 81130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000365

Gnomad OTH exome AF: 0.000227

GnomAD4 exome AF: 0.000203 AC: 284 AN: 1396396 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 139 AN XY: 688834

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000243

Gnomad4 OTH exome AF: 0.000173

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74478

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000259 Hom.: 0

Bravo AF: 0.000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000407 AC: 3

ExAC AF: 0.0000848 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 20, 2021

This sequence change replaces proline with leucine at codon 18 of the GHRHR protein (p.Pro18Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs202243828, ExAC 0.05%). This missense change has been observed in individual(s) with isolated growth hormone deficiency (PMID: 18785993). This variant is also known as c.101C>T. ClinVar contains an entry for this variant (Variation ID: 1031665). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Isolated growth hormone deficiency type IB Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 11, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	11
Dann	Benign	0.77
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.065
Sift	Benign	0.32	T
Sift4G	Benign	0.81	T
Polyphen		0.0090	B
Vest4		0.26
MVP		0.50
MPC		0.092
ClinPred		0.026	T
GERP RS		2.7
Varity_R		0.027
gMVP		0.29

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

Other links and lift over

dbSNP: rs202243828; hg19: chr7-31003736;