chr5-76953174-A-G

Position:

• chr5-76953174-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001882.4(CRHBP):​c.40A>G​(p.Ile14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CRHBP NM_001882.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.130

Genes affected

CRHBP (HGNC:2356): (corticotropin releasing hormone binding protein) Corticotropin-releasing hormone is a potent stimulator of synthesis and secretion of preopiomelanocortin-derived peptides. Although CRH concentrations in the human peripheral circulation are normally low, they increase throughout pregnancy and fall rapidly after parturition. Maternal plasma CRH probably originates from the placenta. Human plasma contains a CRH-binding protein which inactivates CRH and which may prevent inappropriate pituitary-adrenal stimulation in pregnancy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09154785).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRHBP	NM_001882.4	c.40A>G	p.Ile14Val	missense_variant	1/7	ENST00000274368.9	NP_001873.2
CRHBP	XR_948235.4	n.130A>G		non_coding_transcript_exon_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRHBP	ENST00000274368.9	c.40A>G	p.Ile14Val	missense_variant	1/7	1	NM_001882.4	ENSP00000274368	P1
CRHBP	ENST00000506501.1	c.40A>G	p.Ile14Val	missense_variant	1/5	1		ENSP00000426097

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459388 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726030

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2022

The c.40A>G (p.I14V) alteration is located in exon 1 (coding exon 1) of the CRHBP gene. This alteration results from a A to G substitution at nucleotide position 40, causing the isoleucine (I) at amino acid position 14 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.7
DANN	Benign	0.87
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.092	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	0.93	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.063
Sift	Benign	0.52	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.041	B;B
Vest4		0.11
MutPred		0.56		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.11
MPC		0.46
ClinPred		0.22	T
GERP RS		-1.1
Varity_R		0.028
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs1580088679; hg19: chr5-76248999;