chr20-1231594-C-T

Variant names:

• chr20-1231594-C-T
• rs1049749346
• NM_001384355.1:c.343C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001384355.1(RAD21L1):​c.343C>T​(p.His115Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000328 in 1,522,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: RAD21L1 NM_001384355.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18844691).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD21L1	NM_001384355.1	MANE Select	c.343C>T	p.His115Tyr	missense	Exon 4 of 14	NP_001371284.1	A0A804HJ87
	RAD21L1	NM_001136566.3		c.343C>T	p.His115Tyr	missense	Exon 4 of 14	NP_001130038.2	Q9H4I0-1
	RAD21L1	NM_001384356.1		c.-21C>T		5_prime_UTR	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.343C>T	p.His115Tyr	missense	Exon 4 of 14	ENSP00000507397.1	A0A804HJ87
	RAD21L1	ENST00000409241.5	TSL:1	c.343C>T	p.His115Tyr	missense	Exon 4 of 14	ENSP00000386414.1	Q9H4I0-1
	RAD21L1	ENST00000402452.5	TSL:5	c.343C>T	p.His115Tyr	missense	Exon 4 of 14	ENSP00000385925.1	Q9H4I0-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1370662 Hom.: 0 Cov.: 24 AF XY: 0.00000148 AC XY: 1 AN XY: 676780

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

African (AFR) AF: 0.0000323 AC: 1 AN: 30968

American (AMR) AF: 0.00 AC: 0 AN: 34654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24890

East Asian (EAS) AF: 0.00 AC: 0 AN: 35366

South Asian (SAS) AF: 0.00 AC: 0 AN: 76342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1056584

Other (OTH) AF: 0.0000175 AC: 1 AN: 57040

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74318

African (AFR) AF: 0.0000724 AC: 3 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000990 Hom.: 0

Bravo AF: 0.0000869

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	0.076
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.067
Eigen_PC	Benign	0.0059
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.15
Sift	Benign	0.031	D
Sift4G	Uncertain	0.027	D
Polyphen		0.0050	B
Vest4		0.21
MVP		0.092
ClinPred		0.63	D
GERP RS		2.9
Varity_R		0.37
gMVP		0.19
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs1049749346; hg19: chr20-1212238;