9-5339673-G-T

Variant names:

• chr9-5339673-G-T
• rs764553245
• NM_006911.4:c.74C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006911.4(RLN1):​c.74C>A​(p.Ala25Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,460,728 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00059 (2 hom., cov: 27)
  • Exomes 𝑓: 0.00011 (6 hom.)
  • Failed GnomAD Quality Control
• Consequence: RLN1 NM_006911.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.16

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05583644).
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RLN1	NM_006911.4	c.74C>A	p.Ala25Asp	missense_variant	Exon 1 of 2	ENST00000223862.2	NP_008842.1
RLN1	XM_047423703.1	c.74C>A	p.Ala25Asp	missense_variant	Exon 1 of 3		XP_047279659.1
RLN1	XM_047423706.1	c.-48+1148C>A		intron_variant	Intron 1 of 1		XP_047279662.1
RLN1	XM_047423705.1	c.-358C>A		upstream_gene_variant			XP_047279661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RLN1	ENST00000223862.2	c.74C>A	p.Ala25Asp	missense_variant	Exon 1 of 2	1	NM_006911.4	ENSP00000223862.1

Frequencies

GnomAD3 genomes AF: 0.000594 AC: 89 AN: 149918 Hom.: 2 Cov.: 27

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000330

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 251092 AF XY: 0.0000589

Gnomad AFR exome AF: 0.000311

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000107 AC: 156 AN: 1460728 Hom.: 6 Cov.: 31 AF XY: 0.000122 AC XY: 89 AN XY: 726654

Gnomad4 AFR exome AF: 0.000664 AC: 22 AN: 33156

Gnomad4 AMR exome AF: 0.000291 AC: 13 AN: 44680

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.000657 AC: 26 AN: 39598

Gnomad4 SAS exome AF: 0.0000581 AC: 5 AN: 86044

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53418

Gnomad4 NFE exome AF: 0.0000738 AC: 82 AN: 1111576

Gnomad4 Remaining exome AF: 0.000133 AC: 8 AN: 60354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000587 AC: 88 AN: 150038 Hom.: 2 Cov.: 27 AF XY: 0.000599 AC XY: 44 AN XY: 73416

Gnomad4 AFR AF: 0.00147 AC: 0.0014688 AN: 0.0014688

Gnomad4 AMR AF: 0.000330 AC: 0.000329815 AN: 0.000329815

Gnomad4 ASJ AF: 0.000288 AC: 0.000288184 AN: 0.000288184

Gnomad4 EAS AF: 0.00116 AC: 0.00115652 AN: 0.00115652

Gnomad4 SAS AF: 0.000415 AC: 0.000415282 AN: 0.000415282

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000235 AC: 0.000235329 AN: 0.000235329

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000240 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.74C>A (p.A25D) alteration is located in exon 1 (coding exon 1) of the RLN1 gene. This alteration results from a C to A substitution at nucleotide position 74, causing the alanine (A) at amino acid position 25 to be replaced by an aspartic acid (D). 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	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.29
DANN	Benign	0.51
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.022
Sift	Benign	0.64	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.076
MutPred		0.37		Loss of catalytic residue at A25 (P = 0.0098);
MVP		0.061
MPC		0.11
ClinPred		0.0046	T
GERP RS		-1.9
Varity_R		0.089
gMVP		0.10
Mutation Taster		=98/2	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

LitVar

Other links and lift over

dbSNP: rs764553245; hg19: chr9-5339673;