9-5339550-G-A

Position:

• chr9-5339550-G-A

Variant summary

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

The ENST00000223862.2(RLN1):​c.197C>T​(p.Pro66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 26)
• Consequence: RLN1 ENST00000223862.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0410

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]

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=0.13333133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RLN1	NM_006911.4	c.197C>T	p.Pro66Leu	missense_variant	1/2	ENST00000223862.2	NP_008842.1
RLN1	XM_047423703.1	c.197C>T	p.Pro66Leu	missense_variant	1/3		XP_047279659.1
RLN1	XM_047423706.1	c.-48+1271C>T		intron_variant			XP_047279662.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RLN1	ENST00000223862.2	c.197C>T	p.Pro66Leu	missense_variant	1/2	1	NM_006911.4	ENSP00000223862.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 26

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

Feb 27, 2023

The c.197C>T (p.P66L) alteration is located in exon 1 (coding exon 1) of the RLN1 gene. This alteration results from a C to T substitution at nucleotide position 197, causing the proline (P) at amino acid position 66 to be replaced by a leucine (L). 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	0.10
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.16
Sift	Benign	0.20	T
Sift4G	Benign	0.25	T
Polyphen		0.041	B
Vest4		0.095
MutPred		0.32		Loss of disorder (P = 0.0158);
MVP		0.41
MPC		0.090
ClinPred		0.17	T
GERP RS		0.67
Varity_R		0.030
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr9-5339550;