chr17-45830096-G-A

Position:

• chr17-45830096-G-A

Variant summary

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

The NM_004382.5(CRHR1):​c.437G>A​(p.Ser146Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRHR1 NM_004382.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.99

Genes affected

CRHR1 (HGNC:2357): (corticotropin releasing hormone receptor 1) This gene encodes a G-protein coupled receptor that binds neuropeptides of the corticotropin releasing hormone family that are major regulators of the hypothalamic-pituitary-adrenal pathway. The encoded protein is essential for the activation of signal transduction pathways that regulate diverse physiological processes including stress, reproduction, immune response and obesity. Alternative splicing results in multiple transcript variants. Naturally-occurring readthrough transcription between this gene and upstream GeneID:147081 results in transcripts that encode isoforms that share similarity with the products of this gene. [provided by RefSeq, Aug 2016]

LINC02210-CRHR1 (HGNC:):

MAPT-AS1 (HGNC:43738): (MAPT antisense RNA 1) Implicated in Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRHR1	NM_004382.5	c.437G>A	p.Ser146Asn	missense_variant, splice_region_variant	6/13	ENST00000314537.10	NP_004373.2
LINC02210-CRHR1	NM_001256299.3	c.-89G>A		splice_region_variant, 5_prime_UTR_variant	8/15		NP_001243228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRHR1	ENST00000314537.10	c.437G>A	p.Ser146Asn	missense_variant, splice_region_variant	6/13	1	NM_004382.5	ENSP00000326060	P1
MAPT-AS1	ENST00000634876.2	n.604-735C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249404 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135314

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Oct 30, 2023

The c.437G>A (p.S146N) alteration is located in exon 6 (coding exon 6) of the CRHR1 gene. This alteration results from a G to A substitution at nucleotide position 437, causing the serine (S) at amino acid position 146 to be replaced by an asparagine (N). 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	Uncertain	0.47
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0093	T;.;.;.;.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	.;.;.;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.82	N;.;N;N;.;N
REVEL	Uncertain	0.32
Sift	Benign	0.16	T;.;T;T;.;T
Sift4G	Benign	0.16	T;T;T;T;T;T
Polyphen		0.10	B;.;B;B;P;P
Vest4		0.76
MutPred		0.46		.;Loss of MoRF binding (P = 0.1337);.;.;.;Loss of MoRF binding (P = 0.1337);
MVP		0.41
MPC		0.84
ClinPred		0.61	D
GERP RS		5.5
Varity_R		0.81
gMVP		0.63

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: rs1402133730; hg19: chr17-43907462;