NM_000823.4:c.-45C>T

Variant names:

• chr7-30964024-C-T
• rs2302021
• NM_000823.4:c.-45C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000823.4(GHRHR):​c.-45C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.034 in 1,526,688 control chromosomes in the GnomAD database, including 2,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (652 hom., cov: 33)
  • Exomes 𝑓: 0.030 (1681 hom.)
• Consequence: GHRHR NM_000823.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.749
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-30964024-C-T is Benign according to our data. Variant chr7-30964024-C-T is described in ClinVar as Benign. ClinVar VariationId is 360026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

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.-45C>T		5_prime_UTR	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.-45C>T		5_prime_UTR	Exon 1 of 13	ENSP00000320180.2	Q02643
	GHRHR	ENST00000466427.1	TSL:5	n.285-4810C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0672 AC: 10227 AN: 152156 Hom.: 653 Cov.: 33

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.0906

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0626

GnomAD2 exomes AF: 0.0562 AC: 8692 AN: 154790 AF XY: 0.0552

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.0702

Gnomad ASJ exome AF: 0.0241

Gnomad EAS exome AF: 0.173

Gnomad FIN exome AF: 0.0240

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0438

GnomAD4 exome AF: 0.0304 AC: 41719 AN: 1374414 Hom.: 1681 Cov.: 29 AF XY: 0.0315 AC XY: 21419 AN XY: 679484

African (AFR) AF: 0.160 AC: 4976 AN: 31144

American (AMR) AF: 0.0697 AC: 2488 AN: 35682

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 622 AN: 25042

East Asian (EAS) AF: 0.175 AC: 6248 AN: 35636

South Asian (SAS) AF: 0.0814 AC: 6415 AN: 78782

European-Finnish (FIN) AF: 0.0250 AC: 1201 AN: 47948

Middle Eastern (MID) AF: 0.0530 AC: 299 AN: 5638

European-Non Finnish (NFE) AF: 0.0163 AC: 17187 AN: 1057350

Other (OTH) AF: 0.0399 AC: 2283 AN: 57192

GnomAD4 genome AF: 0.0672 AC: 10234 AN: 152274 Hom.: 652 Cov.: 33 AF XY: 0.0692 AC XY: 5150 AN XY: 74456

African (AFR) AF: 0.151 AC: 6276 AN: 41556

American (AMR) AF: 0.0584 AC: 894 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 88 AN: 3472

East Asian (EAS) AF: 0.184 AC: 948 AN: 5158

South Asian (SAS) AF: 0.0900 AC: 434 AN: 4822

European-Finnish (FIN) AF: 0.0259 AC: 275 AN: 10620

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1167 AN: 68026

Other (OTH) AF: 0.0624 AC: 132 AN: 2114

Alfa AF: 0.0372 Hom.: 445

Bravo AF: 0.0748

Asia WGS AF: 0.116 AC: 404 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

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
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.9
DANN	Benign	0.55
PhyloP100		-0.75
PromoterAI		0.023	Neutral
Mutation Taster		=297/3	polymorphism (auto)

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: rs2302021; hg19: chr7-31003639; COSMIC: COSV58196566;