20-1240320-G-T

Variant names:

• chr20-1240320-G-T
• NM_001384355.1:c.743-1G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_001384355.1(RAD21L1):​c.743-1G>T variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000508 in 1,378,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: RAD21L1 NM_001384355.1 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9894
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71

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 Likely_benign. Variant got -2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06834532 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.9, offset of 9, new splice context is: atgttgattatttgaaccAGata. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD21L1	NM_001384355.1	c.743-1G>T		splice_acceptor_variant, intron_variant	Intron 7 of 13	ENST00000683101.1	NP_001371284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD21L1	ENST00000683101.1	c.743-1G>T		splice_acceptor_variant, intron_variant	Intron 7 of 13		NM_001384355.1	ENSP00000507397.1
RAD21L1	ENST00000409241.5	c.743-1G>T		splice_acceptor_variant, intron_variant	Intron 7 of 13	1		ENSP00000386414.1
RAD21L1	ENST00000402452.5	c.743-1G>T		splice_acceptor_variant, intron_variant	Intron 7 of 13	5		ENSP00000385925.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000508 AC: 7 AN: 1378642 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 679016

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: 0.00000653

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	22
DANN	Benign	0.59
Eigen	Uncertain	0.28
Eigen_PC	Benign	-0.022
FATHMM_MKL	Benign	0.72	D
GERP RS		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.52
SpliceAI score (max)		0.77		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.62		Position offset: 10
DS_AL_spliceai		0.77		Position offset: 1

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: chr20-1220964;