NM_000823.4:c.458C>A

Variant names:

• chr7-30971210-C-A
• rs779187338
• NM_000823.4:c.458C>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000823.4(GHRHR):​c.458C>A​(p.Ala153Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GHRHR NM_000823.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.57

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817
• PP5: Variant 7-30971210-C-A is Pathogenic according to our data. Variant chr7-30971210-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30971210-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHRHR	NM_000823.4	c.458C>A	p.Ala153Asp	missense_variant	Exon 5 of 13	ENST00000326139.7	NP_000814.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHRHR	ENST00000326139.7	c.458C>A	p.Ala153Asp	missense_variant	Exon 5 of 13	1	NM_000823.4	ENSP00000320180.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.77e-7 AC: 1 AN: 1286620 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 641052

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000103

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isolated growth hormone deficiency, type 4 Pathogenic:2

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GHRHR c.458C>A (p.Ala153Asp) results in a non-conservative amino acid change located in the G-protein coupled receptors family 2 profile 2 domain (IPR017981) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 162344 control chromosomes. c.458C>A has been reported in the literature in multiple homozygous individuals affected with growth hormone deficiency (e.g., Abouelhoda_2016, Cohen_2019, Monies_2019). These data indicate that the variant is very likely to be associated with disease.The following publications have been ascertained in the context of this evaluation (PMID: 27124789, 31231873, 31130284). ClinVar contains an entry for this variant (Variation ID: 191335). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.21
Sift	Benign	0.13	T;T
Sift4G	Benign	0.20	T;T
Polyphen		1.0	D;D
Vest4		0.74
MutPred		0.66		Gain of sheet (P = 0.0827);.;
MVP		0.57
MPC		0.45
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.72
gMVP		0.62

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: rs779187338; hg19: chr7-31010825;