20-1244118-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001384355.1(RAD21L1):c.1256G>A(p.Gly419Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000591 in 1,549,678 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (1 hom.)
• Consequence: RAD21L1 NM_001384355.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.46

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010977328).
• BP6: Variant 20-1244118-G-A is Benign according to our data. Variant chr20-1244118-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3151012.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD21L1	NM_001384355.1	c.1256G>A	p.Gly419Asp	missense_variant	11/14	ENST00000683101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD21L1	ENST00000683101.1	c.1256G>A	p.Gly419Asp	missense_variant	11/14		NM_001384355.1	A1
RAD21L1	ENST00000409241.5	c.1256G>A	p.Gly419Asp	missense_variant	11/14	1		P4
RAD21L1	ENST00000402452.5	c.1256G>A	p.Gly419Asp	missense_variant	11/14	5

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000192 AC: 30 AN: 156182 Hom.: 0 AF XY: 0.000193 AC XY: 16 AN XY: 82746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000812

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000448

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.000615 AC: 859 AN: 1397368 Hom.: 1 Cov.: 28 AF XY: 0.000617 AC XY: 425 AN XY: 689328

Gnomad4 AFR exome AF: 0.0000951

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: 0.000727

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74482

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000334 Hom.: 0

Bravo AF: 0.000317

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ExAC AF: 0.0000823 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	6.9
Dann	Benign	0.16
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.1	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.92	N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.0	.;B
Vest4		0.033
MVP		0.048
ClinPred		0.014	T
GERP RS		1.7
Varity_R		0.035
gMVP		0.079

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: rs61740338; hg19: chr20-1224762;