7-30964069-A-T

Position:

• chr7-30964069-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000823.4(GHRHR):​c.1A>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GHRHR NM_000823.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.49

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHRHR	NM_000823.4	c.1A>T	p.Met1?	start_lost	1/13	ENST00000326139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHRHR	ENST00000326139.7	c.1A>T	p.Met1?	start_lost	1/13	1	NM_000823.4	P1
GHRHR	ENST00000466427.1	n.285-4765A>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with GHRHR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GHRHR mRNA. The next in-frame methionine is located at codon 5. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.53	N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.082	T
Polyphen		0.73	P
Vest4		0.88
MutPred		0.99		Loss of MoRF binding (P = 0.0816);
MVP		0.45
ClinPred		0.73	D
GERP RS		3.8
Varity_R		0.92
gMVP		0.30

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-31003684;