9-5335342-T-G

Variant names:

• chr9-5335342-T-G
• NM_006911.4:c.467A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006911.4(RLN1):​c.467A>C​(p.His156Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RLN1 NM_006911.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.221

Genes affected

RLN1 (HGNC:10026): (relaxin 1) Relaxins are known endocrine and autocrine/paracrine hormones, belonging to the insulin gene superfamily. In humans there are three non-allelic relaxin genes, RLN1, RLN2 and RLN3, where RLN1 and RLN2 share high sequence homology. The protein encoded by this gene is synthesized as a single-chain polypeptide but the active form consists of an A chain and a B chain linked by disulfide bonds. Relaxin is produced by the ovary, and targets the mammalian reproductive system to ripen the cervix, elongate the pubic symphysis and inhibit uterine contraction. It may have additional roles in enhancing sperm motility, regulating blood pressure, controlling heart rate and releasing oxytocin and vasopressin. [provided by RefSeq, Jan 2013]

RLN2 (HGNC:10027): (relaxin 2) This gene encodes a member of the relaxin subfamily and insulin superfamily of peptide hormones. In humans there are three non-allelic relaxin genes. This gene encodes multiple protein isoforms, at least one of which undergoes proteolytic processing. This processing generates relaxin A and B chains that are linked by disulfide bonds to form the mature peptide hormone. This hormone plays a role in the male and female reproductive systems and was initially noted for its role in pregnancy. This protein also plays broader roles in the cardiovascular system, including in the regulation of blood pressure and control of heart rate, and data from animal models shows that this protein may have anti-fibrotic and cardioprotective effects. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RLN1	NM_006911.4	c.467A>C	p.His156Pro	missense_variant	Exon 2 of 2	ENST00000223862.2	NP_008842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RLN1	ENST00000223862.2	c.467A>C	p.His156Pro	missense_variant	Exon 2 of 2	1	NM_006911.4	ENSP00000223862.1
RLN1	ENST00000487557.2	n.391A>C		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1460916 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726760

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33390

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44634

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26130

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39680

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86050

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53416

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1111536

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.467A>C (p.H156P) alteration is located in exon 2 (coding exon 2) of the RLN1 gene. This alteration results from a A to C substitution at nucleotide position 467, causing the histidine (H) at amino acid position 156 to be replaced by a proline (P). 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	0.12
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Benign	0.24
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.010	D
Polyphen		0.98	D
Vest4		0.32
MutPred		0.70		Gain of glycosylation at H156 (P = 0.0376);
MVP		0.72
MPC		0.52
ClinPred		0.69	D
GERP RS		0.11
Varity_R		0.37
gMVP		0.057
Mutation Taster		=89/11	polymorphism

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: chr9-5335342;