9-5335590-T-G

Position:

• chr9-5335590-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006911.4(RLN1):​c.219A>C​(p.Val73Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00834 in 1,596,512 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (132 hom.)
• Consequence: RLN1 NM_006911.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.264

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]

RLN1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 9-5335590-T-G is Benign according to our data. Variant chr9-5335590-T-G is described in ClinVar as [Benign]. Clinvar id is 718077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.264 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00845 (12201/1444532) while in subpopulation MID AF= 0.0253 (144/5692). AF 95% confidence interval is 0.0219. There are 132 homozygotes in gnomad4_exome. There are 6289 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RLN1	NM_006911.4	c.219A>C	p.Val73Val	synonymous_variant	2/2	ENST00000223862.2	NP_008842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RLN1	ENST00000223862.2	c.219A>C	p.Val73Val	synonymous_variant	2/2	1	NM_006911.4	ENSP00000223862.1
RLN1	ENST00000487557.2	n.143A>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00737 AC: 1119 AN: 151864 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00416

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00918

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00855 AC: 2082 AN: 243530 Hom.: 34 AF XY: 0.00918 AC XY: 1208 AN XY: 131656

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00950

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.0142

Gnomad FIN exome AF: 0.00314

Gnomad NFE exome AF: 0.00940

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.00845 AC: 12201 AN: 1444532 Hom.: 132 Cov.: 29 AF XY: 0.00875 AC XY: 6289 AN XY: 718532

Gnomad4 AFR exome AF: 0.00144

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0139

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.00337

Gnomad4 NFE exome AF: 0.00846

Gnomad4 OTH exome AF: 0.00899

GnomAD4 genome AF: 0.00737 AC: 1120 AN: 151980 Hom.: 23 Cov.: 32 AF XY: 0.00748 AC XY: 556 AN XY: 74286

Gnomad4 AFR AF: 0.00162

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0144

Gnomad4 FIN AF: 0.00416

Gnomad4 NFE AF: 0.00918

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.00648 Hom.: 3

Bravo AF: 0.00790

EpiCase AF: 0.0117

EpiControl AF: 0.0127

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.63
DANN	Benign	0.34

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

LitVar

Other links and lift over

dbSNP: rs35426888; hg19: chr9-5335590;