7-30979237-T-C

Variant names:

• chr7-30979237-T-C
• rs2228078
• NM_000823.4:c.1265T>C

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.1265T>C​(p.Met422Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,613,800 control chromosomes in the GnomAD database, including 2,066 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (255 hom., cov: 33)
  • Exomes 𝑓: 0.023 (1811 hom.)
• Consequence: GHRHR NM_000823.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0660
• Publications: 13 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: Laboratory for Molecular Medicine, Orphanet
• 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 (MetaRNN=0.00125435).
• BP6: Variant 7-30979237-T-C is Benign according to our data. Variant chr7-30979237-T-C is described in ClinVar as Benign. ClinVar VariationId is 360037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.149 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.1265T>C	p.Met422Thr	missense	Exon 13 of 13	NP_000814.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRHR	ENST00000326139.7	TSL:1 MANE Select	c.1265T>C	p.Met422Thr	missense	Exon 13 of 13	ENSP00000320180.2
	GHRHR	ENST00000409904.7	TSL:1	c.1073T>C	p.Met358Thr	missense	Exon 10 of 10	ENSP00000387113.3
	GHRHR	ENST00000409316.5	TSL:1	c.*108T>C		3_prime_UTR	Exon 10 of 10	ENSP00000386602.1

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4402 AN: 152236 Hom.: 252 Cov.: 33

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0370

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0503 AC: 12634 AN: 251138 AF XY: 0.0430

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.00353

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0391

GnomAD4 exome AF: 0.0232 AC: 33972 AN: 1461446 Hom.: 1811 Cov.: 31 AF XY: 0.0231 AC XY: 16767 AN XY: 727034

African (AFR) AF: 0.0117 AC: 393 AN: 33476

American (AMR) AF: 0.243 AC: 10875 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 496 AN: 26124

East Asian (EAS) AF: 0.00262 AC: 104 AN: 39680

South Asian (SAS) AF: 0.0397 AC: 3428 AN: 86242

European-Finnish (FIN) AF: 0.0115 AC: 615 AN: 53314

Middle Eastern (MID) AF: 0.0240 AC: 138 AN: 5752

European-Non Finnish (NFE) AF: 0.0149 AC: 16530 AN: 1111788

Other (OTH) AF: 0.0231 AC: 1393 AN: 60378

GnomAD4 genome AF: 0.0289 AC: 4407 AN: 152354 Hom.: 255 Cov.: 33 AF XY: 0.0310 AC XY: 2313 AN XY: 74502

African (AFR) AF: 0.0147 AC: 612 AN: 41586

American (AMR) AF: 0.154 AC: 2353 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3472

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5180

South Asian (SAS) AF: 0.0364 AC: 176 AN: 4832

European-Finnish (FIN) AF: 0.0134 AC: 142 AN: 10622

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0142 AC: 969 AN: 68034

Other (OTH) AF: 0.0241 AC: 51 AN: 2116

Alfa AF: 0.0174 Hom.: 260

Bravo AF: 0.0396

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.0145 AC: 125

ExAC AF: 0.0410 AC: 4972

Asia WGS AF: 0.0220 AC: 75 AN: 3478

EpiCase AF: 0.0145

EpiControl AF: 0.0153

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.72
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.066
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.077
Sift	Benign	0.20	T
Sift4G	Benign	0.074	T
Polyphen		0.026	B
Vest4		0.038
MPC		0.11
ClinPred		0.00082	T
GERP RS		-0.058
Varity_R		0.055
gMVP		0.51
Mutation Taster		=98/2	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: rs2228078; hg19: chr7-31018852; COSMIC: COSV58198587; COSMIC: COSV58198587;