X-53374723-C-T

Variant names:

• chrX-53374723-C-T
• rs186354950
• NM_006306.4:c.*5380G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006306.4(SMC1A):​c.*5380G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00814 in 112,511 control chromosomes in the GnomAD database, including 6 homozygotes. There are 279 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0081 (6 hom., 277 hem., cov: 22)
  • Exomes 𝑓: 0.011 (0 hom. 2 hem.)
• Consequence: SMC1A NM_006306.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.799
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00813 (912/112155) while in subpopulation SAS AF = 0.0368 (99/2691). AF 95% confidence interval is 0.0309. There are 6 homozygotes in GnomAd4. There are 277 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 912 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.*5380G>A		3_prime_UTR_variant	Exon 25 of 25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.*5380G>A		3_prime_UTR_variant	Exon 26 of 26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.*5380G>A		3_prime_UTR_variant	Exon 25 of 25	1	NM_006306.4	ENSP00000323421.3
SMC1A	ENST00000375340.10	c.*5380G>A		3_prime_UTR_variant	Exon 26 of 26	1		ENSP00000364489.7
SMC1A	ENST00000675504.1	c.*5380G>A		3_prime_UTR_variant	Exon 25 of 25			ENSP00000502524.1

Frequencies

GnomAD3 genomes AF: 0.00816 AC: 915 AN: 112102 Hom.: 6 Cov.: 22

Gnomad AFR AF: 0.00110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00634

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.000278

Gnomad SAS AF: 0.0374

Gnomad FIN AF: 0.00816

Gnomad MID AF: 0.0167

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00663

GnomAD4 exome AF: 0.0112 AC: 4 AN: 356 Hom.: 0 Cov.: 0 AF XY: 0.0139 AC XY: 2 AN XY: 144

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0119 AC: 4 AN: 337

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 16

Other (OTH) AF: 0.00 AC: 0 AN: 3

GnomAD4 genome AF: 0.00813 AC: 912 AN: 112155 Hom.: 6 Cov.: 22 AF XY: 0.00807 AC XY: 277 AN XY: 34309

African (AFR) AF: 0.00110 AC: 34 AN: 30900

American (AMR) AF: 0.00634 AC: 67 AN: 10572

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 32 AN: 2648

East Asian (EAS) AF: 0.000278 AC: 1 AN: 3592

South Asian (SAS) AF: 0.0368 AC: 99 AN: 2691

European-Finnish (FIN) AF: 0.00816 AC: 50 AN: 6125

Middle Eastern (MID) AF: 0.0137 AC: 3 AN: 219

European-Non Finnish (NFE) AF: 0.0116 AC: 616 AN: 53194

Other (OTH) AF: 0.00654 AC: 10 AN: 1528

Alfa AF: 0.0108 Hom.: 59

Bravo AF: 0.00730

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

De Lange syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.81
PhyloP100		0.80
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

Other links and lift over

dbSNP: rs186354950; hg19: chrX-53401644;