X-53374723-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. Variant has been reported in ClinVar as Likely benign (★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant X-53374723-C-T is Benign according to our data. Variant chrX-53374723-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 368546.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC1A	NM_006306.4	c.*5380G>A		3_prime_UTR_variant	25/25	ENST00000322213.9
SMC1A	NM_001281463.1	c.*5380G>A		3_prime_UTR_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC1A	ENST00000322213.9	c.*5380G>A		3_prime_UTR_variant	25/25	1	NM_006306.4	P1
SMC1A	ENST00000375340.10	c.*5380G>A		3_prime_UTR_variant	26/26	1
SMC1A	ENST00000675504.1	c.*5380G>A		3_prime_UTR_variant	25/25

Frequencies

GnomAD3 genomes AF: 0.00816 AC: 915 AN: 112102 Hom.: 6 Cov.: 22 AF XY: 0.00815 AC XY: 279 AN XY: 34246

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

Gnomad4 FIN exome AF: 0.0119

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00110

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.000278

Gnomad4 SAS AF: 0.0368

Gnomad4 FIN AF: 0.00816

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.00654

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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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

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

Publications

LitVar

Other links and lift over

dbSNP: rs186354950; hg19: chrX-53401644;