rs147791932

Variant names:

• chrX-53412268-G-A
• rs147791932
• NM_006306.4:c.855-15C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006306.4(SMC1A):​c.855-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,207,494 control chromosomes in the GnomAD database, including 5 homozygotes. There are 178 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (4 hom., 100 hem., cov: 22)
  • Exomes 𝑓: 0.00027 (1 hom. 78 hem.)
• Consequence: SMC1A NM_006306.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.128
• 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), PanelApp Australia, G2P
• developmental and epileptic encephalopathy, 85, with or without midline brain defects

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-53412268-G-A is Benign according to our data. Variant chrX-53412268-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159964.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00307 (343/111642) while in subpopulation AFR AF = 0.011 (337/30715). AF 95% confidence interval is 0.01. There are 4 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 343 XL,AD 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.855-15C>T		intron	N/A	NP_006297.2
	SMC1A	NM_001281463.1		c.789-15C>T		intron	N/A	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.855-15C>T		intron	N/A	ENSP00000323421.3	Q14683
	SMC1A	ENST00000375340.10	TSL:1	c.789-15C>T		intron	N/A	ENSP00000364489.7	G8JLG1
	SMC1A	ENST00000675504.1		c.789-15C>T		intron	N/A	ENSP00000502524.1	G8JLG1

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 343 AN: 111589 Hom.: 4 Cov.: 22

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000383

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: 0.0000188

Gnomad OTH AF: 0.000667

GnomAD2 exomes AF: 0.000740 AC: 135 AN: 182501 AF XY: 0.000476

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000146

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: 0.000268 AC: 294 AN: 1095852 Hom.: 1 Cov.: 30 AF XY: 0.000216 AC XY: 78 AN XY: 361298

African (AFR) AF: 0.0103 AC: 271 AN: 26352

American (AMR) AF: 0.000114 AC: 4 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19367

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 54057

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40500

Middle Eastern (MID) AF: 0.000254 AC: 1 AN: 3943

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 840233

Other (OTH) AF: 0.000326 AC: 15 AN: 46001

GnomAD4 genome AF: 0.00307 AC: 343 AN: 111642 Hom.: 4 Cov.: 22 AF XY: 0.00295 AC XY: 100 AN XY: 33842

African (AFR) AF: 0.0110 AC: 337 AN: 30715

American (AMR) AF: 0.000383 AC: 4 AN: 10453

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2651

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53151

Other (OTH) AF: 0.000658 AC: 1 AN: 1519

Alfa AF: 0.00234 Hom.: 5

Bravo AF: 0.00332

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	Congenital muscular hypertrophy-cerebral syndrome (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.89
DANN	Benign	0.42
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs147791932;

hg19: chrX-53439218;