19-38876359-T-G

Variant names:

• chr19-38876359-T-G
• NM_001195833.2:c.182A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001195833.2(RINL):​c.182A>C​(p.Glu61Ala) 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. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E61K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RINL NM_001195833.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.760

Genes affected

RINL (HGNC:24795): (Ras and Rab interactor like) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in endocytosis. Predicted to be located in actin cytoskeleton and ruffle. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000269050 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18157151).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RINL	NM_001195833.2	c.182A>C	p.Glu61Ala	missense_variant	Exon 3 of 12	ENST00000591812.2	NP_001182762.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RINL	ENST00000591812.2	c.182A>C	p.Glu61Ala	missense_variant	Exon 3 of 12	2	NM_001195833.2	ENSP00000467107.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.182A>C (p.E61A) alteration is located in exon 3 (coding exon 2) of the RINL gene. This alteration results from a A to C substitution at nucleotide position 182, causing the glutamic acid (E) at amino acid position 61 to be replaced by an alanine (A). 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	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.0017	T
FATHMM_MKL	Benign	0.062	N
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.18	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.76
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.099	T
Vest4		0.30
MVP		0.69
MPC		0.18
GERP RS		0.92
PromoterAI		-0.023	Neutral
Varity_R		0.048
gMVP		0.66
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

Publications

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Other links and lift over

hg19: chr19-39366999;