chr20-1231617-G-A

Variant names:

• chr20-1231617-G-A
• rs2087392392
• NM_001384355.1:c.366G>A

Variant summary

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

The NM_001384356.1(RAD21L1):​c.3G>A​(p.Met1?) variant causes a start lost, 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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: RAD21L1 NM_001384356.1 start_lost, splice_region
• Scores: Splicing: ADA: 0.0001299
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384356.1. 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
	RAD21L1	NM_001384355.1	MANE Select	c.366G>A	p.Met122Ile	missense splice_region	Exon 4 of 14	NP_001371284.1	A0A804HJ87
	RAD21L1	NM_001136566.3		c.366G>A	p.Met122Ile	missense splice_region	Exon 4 of 14	NP_001130038.2	Q9H4I0-1
	RAD21L1	NM_001384356.1		c.3G>A	p.Met1?	start_lost splice_region	Exon 2 of 11	NP_001371285.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD21L1	ENST00000683101.1	MANE Select	c.366G>A	p.Met122Ile	missense splice_region	Exon 4 of 14	ENSP00000507397.1	A0A804HJ87
	RAD21L1	ENST00000409241.5	TSL:1	c.366G>A	p.Met122Ile	missense splice_region	Exon 4 of 14	ENSP00000386414.1	Q9H4I0-1
	RAD21L1	ENST00000402452.5	TSL:5	c.366G>A	p.Met122Ile	missense splice_region	Exon 4 of 14	ENSP00000385925.1	Q9H4I0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000419 AC: 5 AN: 1193784 Hom.: 0 Cov.: 17 AF XY: 0.00000502 AC XY: 3 AN XY: 597230

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

African (AFR) AF: 0.00 AC: 0 AN: 26994

American (AMR) AF: 0.00 AC: 0 AN: 31522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23446

East Asian (EAS) AF: 0.00 AC: 0 AN: 34548

South Asian (SAS) AF: 0.00 AC: 0 AN: 70828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5164

European-Non Finnish (NFE) AF: 0.00000555 AC: 5 AN: 901120

Other (OTH) AF: 0.00 AC: 0 AN: 51152

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000218322), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000376 Hom.: 0

Bravo AF: 0.00000378

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	0.12
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
PhyloP100		1.1
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.046
Sift	Benign	0.15	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.077
MutPred		0.45		Gain of catalytic residue at M122 (P = 0.0165)
MVP		0.040
ClinPred		0.091	T
GERP RS		2.4
Varity_R		0.083
gMVP		0.094
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs2087392392; hg19: chr20-1212261;