5-42719137-A-C

Variant names:

• chr5-42719137-A-C
• rs6180
• NM_000163.5:c.1630A>C

Variant summary

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

The NM_000163.5(GHR):​c.1630A>C​(p.Ile544Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 1,613,300 control chromosomes in the GnomAD database, including 162,936 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I544V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.43 (14368 hom., cov: 32)
  • Exomes 𝑓: 0.45 (148568 hom.)
• Consequence: GHR NM_000163.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 1.58
• Publications: 95 publications found

Genes affected

GHR (HGNC:4263): (growth hormone receptor) This gene encodes a member of the type I cytokine receptor family, which is a transmembrane receptor for growth hormone. Binding of growth hormone to the receptor leads to receptor dimerization and the activation of an intra- and intercellular signal transduction pathway leading to growth. Mutations in this gene have been associated with Laron syndrome, also known as the growth hormone insensitivity syndrome (GHIS), a disorder characterized by short stature. In humans and rabbits, but not rodents, growth hormone binding protein (GHBP) is generated by proteolytic cleavage of the extracellular ligand-binding domain from the mature growth hormone receptor protein. Multiple alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jun 2011]

GHR Gene-Disease associations (from GenCC):

• Laron syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• short stature due to partial GHR deficiency

  Inheritance: Unknown, AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2171396E-4).
• BP6: Variant 5-42719137-A-C is Benign according to our data. Variant chr5-42719137-A-C is described in ClinVar as Benign. ClinVar VariationId is 8658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000163.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	NM_000163.5	MANE Select	c.1630A>C	p.Ile544Leu	missense	Exon 10 of 10	NP_000154.1
	GHR	NM_001242399.2		c.1651A>C	p.Ile551Leu	missense	Exon 10 of 10	NP_001229328.1
	GHR	NM_001242400.2		c.1630A>C	p.Ile544Leu	missense	Exon 11 of 11	NP_001229329.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHR	ENST00000230882.9	TSL:1 MANE Select	c.1630A>C	p.Ile544Leu	missense	Exon 10 of 10	ENSP00000230882.4
	GHR	ENST00000620156.4	TSL:5	c.1651A>C	p.Ile551Leu	missense	Exon 10 of 10	ENSP00000483403.1
	GHR	ENST00000537449.5	TSL:5	c.1630A>C	p.Ile544Leu	missense	Exon 10 of 10	ENSP00000442206.2

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65445 AN: 151868 Hom.: 14380 Cov.: 32

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.434

GnomAD2 exomes AF: 0.436 AC: 109339 AN: 250692 AF XY: 0.442

Gnomad AFR exome AF: 0.387

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.432

Gnomad EAS exome AF: 0.599

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.455

Gnomad OTH exome AF: 0.454

GnomAD4 exome AF: 0.449 AC: 656062 AN: 1461314 Hom.: 148568 Cov.: 40 AF XY: 0.450 AC XY: 327308 AN XY: 726956

African (AFR) AF: 0.390 AC: 13066 AN: 33476

American (AMR) AF: 0.335 AC: 14962 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 11407 AN: 26134

East Asian (EAS) AF: 0.580 AC: 23038 AN: 39694

South Asian (SAS) AF: 0.463 AC: 39939 AN: 86236

European-Finnish (FIN) AF: 0.374 AC: 19965 AN: 53408

Middle Eastern (MID) AF: 0.478 AC: 2758 AN: 5768

European-Non Finnish (NFE) AF: 0.453 AC: 503417 AN: 1111520

Other (OTH) AF: 0.456 AC: 27510 AN: 60382

GnomAD4 genome AF: 0.431 AC: 65438 AN: 151986 Hom.: 14368 Cov.: 32 AF XY: 0.431 AC XY: 31996 AN XY: 74270

African (AFR) AF: 0.390 AC: 16180 AN: 41478

American (AMR) AF: 0.390 AC: 5951 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1543 AN: 3470

East Asian (EAS) AF: 0.576 AC: 2960 AN: 5138

South Asian (SAS) AF: 0.478 AC: 2295 AN: 4798

European-Finnish (FIN) AF: 0.371 AC: 3913 AN: 10554

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.459 AC: 31186 AN: 67962

Other (OTH) AF: 0.432 AC: 909 AN: 2106

Alfa AF: 0.452 Hom.: 64890

Bravo AF: 0.430

TwinsUK AF: 0.446 AC: 1654

ALSPAC AF: 0.446 AC: 1717

ESP6500AA AF: 0.389 AC: 1714

ESP6500EA AF: 0.461 AC: 3961

ExAC AF: 0.443 AC: 53769

Asia WGS AF: 0.530 AC: 1843 AN: 3478

EpiCase AF: 0.474

EpiControl AF: 0.466

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Laron-type isolated somatotropin defect (3)
-	-	3	not provided (3)
-	-	1	Short stature due to partial GHR deficiency (1)
-	-	-	Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.00012	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.6
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.10
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.13	T
Polyphen		0.93	P
Vest4		0.14
MPC		0.28
ClinPred		0.066	T
GERP RS		3.4
Varity_R		0.16
gMVP		0.34
Mutation Taster		=97/3	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: rs6180; hg19: chr5-42719239; COSMIC: COSV50112820; COSMIC: COSV50112820;