rs28364018

Variant names:

• chr8-66177635-T-G
• rs28364018
• NM_000756.4:c.-14-144A>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000756.4(CRH):​c.-14-144A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.04 in 1,210,714 control chromosomes in the GnomAD database, including 1,105 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.040 (158 hom., cov: 32)
  • Exomes 𝑓: 0.040 (947 hom.)
• Consequence: CRH NM_000756.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.16

Genes affected

CRH (HGNC:2355): (corticotropin releasing hormone) This gene encodes a member of the corticotropin-releasing factor family. The encoded preproprotein is proteolytically processed to generate the mature neuropeptide hormone. In response to stress, this hormone is secreted by the paraventricular nucleus (PVN) of the hypothalamus, binds to corticotropin releasing hormone receptors and stimulates the release of adrenocorticotropic hormone from the pituitary gland. Marked reduction in this protein has been observed in association with Alzheimer's disease. Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia and hepatitis. In addition to production in the hypothalamus, this protein is also synthesized in peripheral tissues, such as T lymphocytes, and is highly expressed in the placenta. In the placenta it is a marker that determines the length of gestation and the timing of parturition and delivery. A rapid increase in circulating levels of the hormone occurs at the onset of parturition, suggesting that, in addition to its metabolic functions, this protein may act as a trigger for parturition. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRH	NM_000756.4	c.-14-144A>C		intron_variant	Intron 1 of 1	ENST00000276571.5	NP_000747.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRH	ENST00000276571.5	c.-14-144A>C		intron_variant	Intron 1 of 1	1	NM_000756.4	ENSP00000276571.3

Frequencies

GnomAD3 genomes AF: 0.0402 AC: 6110 AN: 152056 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.0360

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0427

Gnomad ASJ AF: 0.0528

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.00850

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0477

Gnomad OTH AF: 0.0431

GnomAD4 exome AF: 0.0400 AC: 42370 AN: 1058542 Hom.: 947 AF XY: 0.0395 AC XY: 20502 AN XY: 519652

Gnomad4 AFR exome AF: 0.0318

Gnomad4 AMR exome AF: 0.0328

Gnomad4 ASJ exome AF: 0.0464

Gnomad4 EAS exome AF: 0.00809

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.0185

Gnomad4 NFE exome AF: 0.0441

Gnomad4 OTH exome AF: 0.0390

GnomAD4 genome AF: 0.0402 AC: 6115 AN: 152172 Hom.: 158 Cov.: 32 AF XY: 0.0393 AC XY: 2923 AN XY: 74416

Gnomad4 AFR AF: 0.0361

Gnomad4 AMR AF: 0.0427

Gnomad4 ASJ AF: 0.0528

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.00851

Gnomad4 FIN AF: 0.0252

Gnomad4 NFE AF: 0.0477

Gnomad4 OTH AF: 0.0427

Alfa AF: 0.0427 Hom.: 23

Bravo AF: 0.0410

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.010
DANN	Benign	0.35

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: rs28364018; hg19: chr8-67089870;