7-30971210-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000823.4(GHRHR):​c.458C>T​(p.Ala153Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000233 in 1,286,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A153D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: GHRHR NM_000823.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57
• Publications: 3 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: Orphanet, Laboratory for Molecular Medicine
• isolated growth hormone deficiency, type 4

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-30971210-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 191335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22146896).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000823.4. 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.458C>T	p.Ala153Val	missense	Exon 5 of 13	NP_000814.2	A0A090N8Y6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRHR	ENST00000326139.7	TSL:1 MANE Select	c.458C>T	p.Ala153Val	missense	Exon 5 of 13	ENSP00000320180.2	Q02643
	GHRHR	ENST00000409904.7	TSL:1	c.266C>T	p.Ala89Val	missense	Exon 2 of 10	ENSP00000387113.3	Q9HB45
	GHRHR	ENST00000409316.5	TSL:1	c.-90C>T		5_prime_UTR	Exon 3 of 10	ENSP00000386602.1	Q9HB43

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000123 AC: 2 AN: 162344 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000313

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000233 AC: 3 AN: 1286616 Hom.: 0 Cov.: 20 AF XY: 0.00000312 AC XY: 2 AN XY: 641050

African (AFR) AF: 0.00 AC: 0 AN: 29762

American (AMR) AF: 0.00 AC: 0 AN: 36130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24562

East Asian (EAS) AF: 0.00 AC: 0 AN: 35816

South Asian (SAS) AF: 0.00 AC: 0 AN: 77186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5484

European-Non Finnish (NFE) AF: 0.00000308 AC: 3 AN: 973834

Other (OTH) AF: 0.00 AC: 0 AN: 54288

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000202 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000911 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.044
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.62	N
PhyloP100		1.6
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.13
Sift	Benign	0.39	T
Sift4G	Benign	0.52	T
Polyphen		0.99	D
Vest4		0.25
MutPred		0.51		Loss of catalytic residue at A153 (P = 0.1285)
MVP		0.50
MPC		0.24
ClinPred		0.76	D
GERP RS		5.3
Varity_R		0.17
gMVP		0.28
Mutation Taster		=57/43	polymorphism

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: rs779187338; hg19: chr7-31010825;