7-30964078-C-T

Variant names:

• chr7-30964078-C-T
• rs142361839
• NM_000823.4:c.10C>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.10C>T​(p.Arg4Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000625 in 1,550,560 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (1 hom.)
• Consequence: GHRHR NM_000823.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.548
• 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=0.0069287717).

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.10C>T	p.Arg4Trp	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.10C>T	p.Arg4Trp	missense	Exon 1 of 13	ENSP00000320180.2	Q02643
	GHRHR	ENST00000466427.1	TSL:5	n.285-4756C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000670 AC: 104 AN: 155284 AF XY: 0.000709

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000727

Gnomad ASJ exome AF: 0.00141

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000662

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000639 AC: 893 AN: 1398238 Hom.: 1 Cov.: 32 AF XY: 0.000648 AC XY: 447 AN XY: 689666

African (AFR) AF: 0.000127 AC: 4 AN: 31592

American (AMR) AF: 0.000756 AC: 27 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 30 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00102 AC: 81 AN: 79228

European-Finnish (FIN) AF: 0.0000829 AC: 4 AN: 48250

Middle Eastern (MID) AF: 0.00266 AC: 15 AN: 5644

European-Non Finnish (NFE) AF: 0.000651 AC: 702 AN: 1078928

Other (OTH) AF: 0.000517 AC: 30 AN: 57972

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74492

African (AFR) AF: 0.0000481 AC: 2 AN: 41582

American (AMR) AF: 0.00157 AC: 24 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

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

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000737 Hom.: 2

Bravo AF: 0.000506

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000797 AC: 6

ExAC AF: 0.000384 AC: 21

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.90
DANN	Benign	0.77
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.55
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.044
Sift	Benign	0.17	T
Sift4G	Uncertain	0.012	D
Polyphen		0.0040	B
Vest4		0.13
MVP		0.20
MPC		0.093
ClinPred		0.013	T
GERP RS		-6.9
PromoterAI		-0.14	Neutral
Varity_R		0.030
gMVP		0.42
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142361839; hg19: chr7-31003693;