dbSNP rs35609199: GHRHR:c.598-10T>C (chr7-30973975-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000823.4(GHRHR):c.598-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 1,612,620 control chromosomes in the GnomAD database, including 4,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1704 hom., cov: 32)

Exomes 𝑓: 0.041 ( 2639 hom. )

Consequence

GHRHR
NM_000823.4 intron

Scores

Splicing: ADA: 0.00009625

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.29

Publications

7 publications found

Variant links:

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)

GHRHR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 7-30973975-T-C is Benign according to our data. Variant chr7-30973975-T-C is described in ClinVar as Benign. ClinVar VariationId is 360031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.271 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.598-10T>C		intron	N/A	NP_000814.2	A0A090N8Y6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GHRHR	ENST00000326139.7	TSL:1 MANE Select	c.598-10T>C	intron	N/A	ENSP00000320180.2	Q02643
GHRHR	ENST00000409904.7	TSL:1	c.406-10T>C	intron	N/A	ENSP00000387113.3	Q9HB45
GHRHR	ENST00000409316.5	TSL:1	c.51-454T>C	intron	N/A	ENSP00000386602.1	Q9HB43

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15914

AN:

151694

Hom.:

1700

Cov.:

show subpopulations

Gnomad AFR

AF:

0.275

Gnomad AMI

AF:

0.114

Gnomad AMR

AF:

0.0565

Gnomad ASJ

AF:

0.0817

Gnomad EAS

AF:

0.0696

Gnomad SAS

AF:

0.0915

Gnomad FIN

AF:

0.0312

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.0290

Gnomad OTH

AF:

0.0872

GnomAD2 exomes

AF:

0.0619

AC:

15392

AN:

248662

AF XY:

0.0600

show subpopulations

Gnomad AFR exome

AF:

0.279

Gnomad AMR exome

AF:

0.0369

Gnomad ASJ exome

AF:

0.0784

Gnomad EAS exome

AF:

0.0742

Gnomad FIN exome

AF:

0.0325

Gnomad NFE exome

AF:

0.0306

Gnomad OTH exome

AF:

0.0604

GnomAD4 exome

AF:

0.0408

AC:

59557

AN:

1460808

Hom.:

2639

Cov.:

AF XY:

0.0421

AC XY:

30607

AN XY:

726740

show subpopulations

African (AFR)

AF:

0.283

AC:

9461

AN:

33476

American (AMR)

AF:

0.0393

AC:

1757

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0756

AC:

1977

AN:

26134

East Asian (EAS)

AF:

0.0511

AC:

2030

AN:

39694

South Asian (SAS)

AF:

0.0941

AC:

8116

AN:

86252

European-Finnish (FIN)

AF:

0.0342

AC:

1795

AN:

52554

Middle Eastern (MID)

AF:

0.113

AC:

651

AN:

5766

European-Non Finnish (NFE)

AF:

0.0271

AC:

30162

AN:

1111826

Other (OTH)

AF:

0.0597

AC:

3608

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2910

5820

8729

11639

14549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1338

2676

4014

5352

6690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.105

AC:

15934

AN:

151812

Hom.:

1704

Cov.:

AF XY:

0.104

AC XY:

7740

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.275

AC:

11369

AN:

41320

American (AMR)

AF:

0.0564

AC:

862

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0817

AC:

283

AN:

3466

East Asian (EAS)

AF:

0.0698

AC:

359

AN:

5144

South Asian (SAS)

AF:

0.0910

AC:

433

AN:

4760

European-Finnish (FIN)

AF:

0.0312

AC:

331

AN:

10596

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0290

AC:

1971

AN:

67936

Other (OTH)

AF:

0.0867

AC:

183

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

611

1222

1833

2444

3055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0815

Hom.:

391

Bravo

AF:

0.116

Asia WGS

AF:

0.100

AC:

350

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

GHRHR-related disorder (1)

Isolated growth hormone deficiency type IB (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.0

(source)

DANN

Benign

0.40

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000096

dbscSNV1_RF

Benign

0.0060

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over