rs1556885815

Variant names:

• chrX-53381057-A-C
• rs1556885815
• NM_006306.4:c.3468T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_006306.4(SMC1A):​c.3468T>G​(p.Asp1156Glu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0034 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SMC1A NM_006306.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 4.38
• Publications: 0 publications found

Genes affected

SMC1A (HGNC:11111): (structural maintenance of chromosomes 1A) Proper cohesion of sister chromatids is a prerequisite for the correct segregation of chromosomes during cell division. The cohesin multiprotein complex is required for sister chromatid cohesion. This complex is composed partly of two structural maintenance of chromosomes (SMC) proteins, SMC3 and either SMC1B or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with BRCA1 and is phosphorylated by ATM, indicating a potential role for this protein in DNA repair. This gene, which belongs to the SMC gene family, is located in an area of the X-chromosome that escapes X inactivation. Mutations in this gene result in Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

SMC1A Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• developmental and epileptic encephalopathy, 85, with or without midline brain defects

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cornelia de Lange syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_006306.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006306.4. 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
	SMC1A	NM_006306.4	MANE Select	c.3468T>G	p.Asp1156Glu	missense	Exon 23 of 25	NP_006297.2
	SMC1A	NM_001281463.1		c.3402T>G	p.Asp1134Glu	missense	Exon 24 of 26	NP_001268392.1	G8JLG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC1A	ENST00000322213.9	TSL:1 MANE Select	c.3468T>G	p.Asp1156Glu	missense	Exon 23 of 25	ENSP00000323421.3	Q14683
	SMC1A	ENST00000375340.10	TSL:1	c.3402T>G	p.Asp1134Glu	missense	Exon 24 of 26	ENSP00000364489.7	G8JLG1
	SMC1A	ENST00000675504.1		c.3402T>G	p.Asp1134Glu	missense	Exon 23 of 25	ENSP00000502524.1	G8JLG1

Frequencies

GnomAD3 genomes AF: 0.0000368 AC: 4 AN: 108590 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

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: 0.000354

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000383

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00340 AC: 3575 AN: 1052218 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 341022

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

African (AFR) AF: 0.00259 AC: 66 AN: 25478

American (AMR) AF: 0.000201 AC: 7 AN: 34781

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 23 AN: 18727

East Asian (EAS) AF: 0.000590 AC: 17 AN: 28790

South Asian (SAS) AF: 0.00127 AC: 68 AN: 53376

European-Finnish (FIN) AF: 0.000102 AC: 4 AN: 39253

Middle Eastern (MID) AF: 0.000497 AC: 2 AN: 4022

European-Non Finnish (NFE) AF: 0.00405 AC: 3254 AN: 803542

Other (OTH) AF: 0.00303 AC: 134 AN: 44249

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000368 AC: 4 AN: 108649 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 31405

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

African (AFR) AF: 0.00 AC: 0 AN: 29932

American (AMR) AF: 0.00 AC: 0 AN: 10213

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2595

East Asian (EAS) AF: 0.00 AC: 0 AN: 3373

South Asian (SAS) AF: 0.00 AC: 0 AN: 2401

European-Finnish (FIN) AF: 0.000354 AC: 2 AN: 5642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000384 AC: 2 AN: 52150

Other (OTH) AF: 0.00 AC: 0 AN: 1468

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital muscular hypertrophy-cerebral syndrome (1)
-	1	-	Congenital muscular hypertrophy-cerebral syndrome;C5393312:Developmental and epileptic encephalopathy, 85, with or without midline brain defects (1)
-	1	-	Developmental and epileptic encephalopathy, 85, with or without midline brain defects (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.87		Loss of catalytic residue at D1159 (P = 0.2854)
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		1.0
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1556885815; hg19: chrX-53407978;