9-5339664-T-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_006911.4(RLN1):c.83A>T(p.Lys28Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00054 (1 hom., cov: 27)
  • Exomes 𝑓: 0.000063 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: RLN1 NM_006911.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.579

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047902405).
• BP6: Variant 9-5339664-T-A is Benign according to our data. Variant chr9-5339664-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 2363928.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RLN1	NM_006911.4	c.83A>T	p.Lys28Met	missense_variant	1/2	ENST00000223862.2
RLN1	XM_047423703.1	c.83A>T	p.Lys28Met	missense_variant	1/3
RLN1	XM_047423706.1	c.-48+1157A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RLN1	ENST00000223862.2	c.83A>T	p.Lys28Met	missense_variant	1/2	1	NM_006911.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 82 AN: 150470 Hom.: 1 Cov.: 27 FAILED QC

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000330

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000630 AC: 92 AN: 1460884 Hom.: 5 Cov.: 31 AF XY: 0.0000757 AC XY: 55 AN XY: 726742

Gnomad4 AFR exome AF: 0.000453

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000555

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000538 AC: 81 AN: 150584 Hom.: 1 Cov.: 27 AF XY: 0.000570 AC XY: 42 AN XY: 73634

Gnomad4 AFR AF: 0.00133

Gnomad4 AMR AF: 0.000329

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000192 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.29
DANN	Benign	0.67
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00032	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.77	N
REVEL	Benign	0.020
Sift	Benign	0.15	T
Sift4G	Benign	0.11	T
Polyphen		0.0060	B
Vest4		0.12
MutPred		0.15		Loss of ubiquitination at K28 (P = 0.0309);
MVP		0.12
MPC		0.095
ClinPred		0.019	T
GERP RS		-1.9
Varity_R		0.090
gMVP		0.19

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: rs397780021; hg19: chr9-5339664;