NM_006911.4:c.77A>C

Variant names:

• chr9-5339670-T-G
• rs369616777
• NM_006911.4:c.77A>C

Variant summary

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

The NM_006911.4(RLN1):​c.77A>C​(p.Lys26Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000815 in 1,460,760 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (2 hom., cov: 27)
  • Exomes 𝑓: 0.000081 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: RLN1 NM_006911.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.23
• Publications: 1 publications found

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=0.051811486).
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006911.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RLN1	NM_006911.4	MANE Select	c.77A>C	p.Lys26Thr	missense	Exon 1 of 2	NP_008842.1	P04808-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RLN1	ENST00000223862.2	TSL:1 MANE Select	c.77A>C	p.Lys26Thr	missense	Exon 1 of 2	ENSP00000223862.1	P04808-1

Frequencies

GnomAD3 genomes AF: 0.000586 AC: 88 AN: 150084 Hom.: 2 Cov.: 27

Gnomad AFR AF: 0.00144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000330

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000478 AC: 12 AN: 251106 AF XY: 0.0000442

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000815 AC: 119 AN: 1460760 Hom.: 5 Cov.: 31 AF XY: 0.0000881 AC XY: 64 AN XY: 726654

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000513 AC: 17 AN: 33160

American (AMR) AF: 0.000269 AC: 12 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000581 AC: 23 AN: 39600

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1111572

Other (OTH) AF: 0.000133 AC: 8 AN: 60362

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (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: 0.000579 AC: 87 AN: 150204 Hom.: 2 Cov.: 27 AF XY: 0.000585 AC XY: 43 AN XY: 73460

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00144 AC: 57 AN: 39666

American (AMR) AF: 0.000330 AC: 5 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5182

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2098

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000225 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.12
DANN	Benign	0.68
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		-2.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.0050
Sift	Benign	0.30	T
Sift4G	Benign	0.12	T
Polyphen		0.027	B
Vest4		0.13
MutPred		0.36		Loss of ubiquitination at K26 (P = 0.027)
MVP		0.040
MPC		0.088
ClinPred		0.062	T
GERP RS		-5.0
PromoterAI		-0.021	Neutral
Varity_R		0.031
gMVP		0.12
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs369616777; hg19: chr9-5339670;