9-5335342-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/21 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:):

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	UniProt
RLN1	NM_006911.4	c.467A>C	p.His156Pro	missense_variant	2/2	ENST00000223862.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RLN1	ENST00000223862.2	c.467A>C	p.His156Pro	missense_variant	2/2	1	NM_006911.4	P1
RLN1	ENST00000487557.2	n.391A>C		non_coding_transcript_exon_variant	2/2	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

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.: 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

Apr 22, 2022

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
MutationTaster	Benign	1.0	N;N
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

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;