7-30964121-C-T

Variant names:

• chr7-30964121-C-T
• rs202243828
• NM_000823.4:c.53C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P18P) has been classified as Likely benign.

• 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
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050522536).

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.53C>T	p.Pro18Leu	missense	Exon 1 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.53C>T	p.Pro18Leu	missense	Exon 1 of 13	ENSP00000320180.2	Q02643
	GHRHR	ENST00000466427.1	TSL:5	n.285-4713C>T		intron	N/A

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

GnomAD2 exomes AF: 0.000182 AC: 28 AN: 153766 AF XY: 0.000173

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 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

African (AFR) AF: 0.0000317 AC: 1 AN: 31586

American (AMR) AF: 0.000224 AC: 8 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5456

European-Non Finnish (NFE) AF: 0.000243 AC: 262 AN: 1078848

Other (OTH) AF: 0.000173 AC: 10 AN: 57948

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

African (AFR) AF: 0.000120 AC: 5 AN: 41566

American (AMR) AF: 0.000784 AC: 12 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000272 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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.26
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
PromoterAI		-0.018	Neutral
Varity_R		0.027
gMVP		0.29
Mutation Taster		=95/5	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: rs202243828; hg19: chr7-31003736;