rs377270943

Variant names:

• chrX-53409058-T-G
• rs377270943
• NM_006306.4:c.1545+4A>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_006306.4(SMC1A):​c.1545+4A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,206,279 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 71 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 21 hem., cov: 22)
  • Exomes 𝑓: 0.00015 (0 hom. 50 hem.)
• Consequence: SMC1A NM_006306.4 splice_region, intron
• Scores: Splicing: ADA: 0.9801
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.97
• 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: G2P, Labcorp Genetics (formerly Invitae)
• developmental and epileptic encephalopathy, 85, with or without midline brain defects

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant X-53409058-T-G is Benign according to our data. Variant chrX-53409058-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159942.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00118 (131/111266) while in subpopulation AFR AF = 0.00414 (127/30671). AF 95% confidence interval is 0.00356. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 131 AD,XL gene.

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.1545+4A>C		splice_region intron	N/A	NP_006297.2
	SMC1A	NM_001281463.1		c.1479+4A>C		splice_region intron	N/A	NP_001268392.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC1A	ENST00000322213.9	TSL:1 MANE Select	c.1545+4A>C		splice_region intron	N/A	ENSP00000323421.3
	SMC1A	ENST00000375340.10	TSL:1	c.1479+4A>C		splice_region intron	N/A	ENSP00000364489.7
	SMC1A	ENST00000675504.1		c.1479+4A>C		splice_region intron	N/A	ENSP00000502524.1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 132 AN: 111213 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000289

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: 0.000679

GnomAD2 exomes AF: 0.000386 AC: 70 AN: 181456 AF XY: 0.000300

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.000401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000145 AC: 159 AN: 1095013 Hom.: 0 Cov.: 30 AF XY: 0.000139 AC XY: 50 AN XY: 360499

African (AFR) AF: 0.00494 AC: 130 AN: 26341

American (AMR) AF: 0.000341 AC: 12 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.00 AC: 0 AN: 54075

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40359

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3980

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 839521

Other (OTH) AF: 0.000283 AC: 13 AN: 45975

GnomAD4 genome AF: 0.00118 AC: 131 AN: 111266 Hom.: 0 Cov.: 22 AF XY: 0.000628 AC XY: 21 AN XY: 33442

African (AFR) AF: 0.00414 AC: 127 AN: 30671

American (AMR) AF: 0.000289 AC: 3 AN: 10396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3513

South Asian (SAS) AF: 0.00 AC: 0 AN: 2666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53013

Other (OTH) AF: 0.000671 AC: 1 AN: 1491

Alfa AF: 0.00133 Hom.: 11

Bravo AF: 0.00125

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	1	Congenital muscular hypertrophy-cerebral syndrome (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.93
PhyloP100		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.10		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: rs377270943; hg19: chrX-53435989;