Genetic Variant RAD21L1:c.743-1G>T (chr20-1240320-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_ModerateBS2

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

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384355.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RAD21L1	NM_001384355.1	MANE Select	c.743-1G>T	splice_acceptor intron	N/A	NP_001371284.1	A0A804HJ87
RAD21L1	NM_001136566.3		c.743-1G>T	splice_acceptor intron	N/A	NP_001130038.2	Q9H4I0-1
RAD21L1	NM_001384356.1		c.379+913G>T	intron	N/A	NP_001371285.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RAD21L1	ENST00000683101.1	MANE Select	c.743-1G>T	splice_acceptor intron	N/A	ENSP00000507397.1	A0A804HJ87
RAD21L1	ENST00000409241.5	TSL:1	c.743-1G>T	splice_acceptor intron	N/A	ENSP00000386414.1	Q9H4I0-1
RAD21L1	ENST00000402452.5	TSL:5	c.743-1G>T	splice_acceptor intron	N/A	ENSP00000385925.1	Q9H4I0-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000508

AC:

AN:

1378642

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

679016

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30400

American (AMR)

AF:

0.00

AC:

AN:

31278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24760

East Asian (EAS)

AF:

0.00

AC:

AN:

34842

South Asian (SAS)

AF:

0.00

AC:

AN:

73852

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.00000653

AC:

AN:

1071716

Other (OTH)

AF:

0.00

AC:

AN:

57158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.59

Eigen

Uncertain

0.28

Eigen_PC

Benign

-0.022

FATHMM_MKL

Benign

0.72

PhyloP100

1.7

GERP RS

2.3

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over