Variant 20-1231617-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_StrongBS2

The NM_001384355.1(RAD21L1):c.366G>A(p.Met122Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000419 in 1,193,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. M122T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

RAD21L1
NM_001384355.1 missense, splice_region

Scores

Splicing: ADA: 0.0001299

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11

Variant links:

Genes affected

RAD21L1 (HGNC:16271): (RAD21 cohesin complex component like 1) Predicted to enable chromatin binding activity. Predicted to be involved in mitotic sister chromatid cohesion; replication-born double-strand break repair via sister chromatid exchange; and synaptonemal complex assembly. Predicted to act upstream of or within several processes, including double-strand break repair via homologous recombination; homologous chromosome segregation; and seminiferous tubule development. Predicted to be located in lateral element. Predicted to be part of nuclear meiotic cohesin complex and nuclear mitotic cohesin complex. Predicted to be active in synaptonemal complex. [provided by Alliance of Genome Resources, Apr 2022]

RAD21L1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046407014).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD21L1	NM_001384355.1 linkuse as main transcript	c.366G>A	p.Met122Ile	missense_variant, splice_region_variant	4/14	ENST00000683101.1	NP_001371284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD21L1	ENST00000683101.1 linkuse as main transcript	c.366G>A	p.Met122Ile	missense_variant, splice_region_variant	4/14		NM_001384355.1	ENSP00000507397	A1
RAD21L1	ENST00000409241.5 linkuse as main transcript	c.366G>A	p.Met122Ile	missense_variant, splice_region_variant	4/14	1		ENSP00000386414	P4	Q9H4I0-1
RAD21L1	ENST00000402452.5 linkuse as main transcript	c.366G>A	p.Met122Ile	missense_variant, splice_region_variant	4/14	5		ENSP00000385925		Q9H4I0-2
RAD21L1	ENST00000477283.1 linkuse as main transcript	n.528G>A		splice_region_variant, non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000419

AC:

AN:

1193784

Hom.:

Cov.:

AF XY:

0.00000502

AC XY:

AN XY:

597230

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000555

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000376

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

The c.366G>A (p.M122I) alteration is located in exon 4 (coding exon 3) of the RAD21L1 gene. This alteration results from a G to A substitution at nucleotide position 366, causing the methionine (M) at amino acid position 122 to be replaced by an isoleucine (I). 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

0.12

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.051

.;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.51

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.32

T;T

M_CAP

Benign

0.0034

MetaRNN

Benign

0.046

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.050

N;N

REVEL

Benign

0.046

Sift

Benign

0.15

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0

.;B

Vest4

0.077

MutPred

0.45

Gain of catalytic residue at M122 (P = 0.0165);Gain of catalytic residue at M122 (P = 0.0165);

MVP

0.040

ClinPred

0.091

GERP RS

2.4

Varity_R

0.083

gMVP

0.094

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00013

dbscSNV1_RF

Benign

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over