chr19-14028370-G-C

Position:

• chr19-14028370-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_080864.4(RLN3):​c.166G>C​(p.Asp56His) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RLN3 NM_080864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57

Genes affected

RLN3 (HGNC:17135): (relaxin 3) This gene encodes a member of the relaxin family of insulin-like hormones that is expressed predominantly in the brain and plays a role in physiological processes such as stress, memory and appetite regulation. The encoded protein is a precursor that is proteolytically processed to generate a heterodimeric mature form consisting A and B chains interlinked by disulfide bonds. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3615691).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RLN3	NM_080864.4	c.166G>C	p.Asp56His	missense_variant	1/2	ENST00000431365.3
RLN3	NM_001311197.2	c.166G>C	p.Asp56His	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RLN3	ENST00000431365.3	c.166G>C	p.Asp56His	missense_variant	1/2	1	NM_080864.4	P1
RLN3	ENST00000585987.1	c.166G>C	p.Asp56His	missense_variant	1/3	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Mar 11, 2022

The c.166G>C (p.D56H) alteration is located in exon 1 (coding exon 1) of the RLN3 gene. This alteration results from a G to C substitution at nucleotide position 166, causing the aspartic acid (D) at amino acid position 56 to be replaced by a histidine (H). 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	0.21
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.0077
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.26
Sift	Benign	0.056	T;.
Sift4G	Benign	0.11	T;D
Polyphen		0.99	D;.
Vest4		0.44
MutPred		0.27		Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);
MVP		0.86
MPC		0.40
ClinPred		0.80	D
GERP RS		3.1
Varity_R		0.19
gMVP		0.43

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: chr19-14139182;