X-53375149-GGT-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_006306.4(SMC1A):c.*4952_*4953del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 112,402 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 113 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., 113 hem., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SMC1A NM_006306.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.458

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 -10 ACMG points.

• BP6: Variant X-53375149-GGT-G is Benign according to our data. Variant chrX-53375149-GGT-G is described in ClinVar as [Likely_benign]. Clinvar id is 368551.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00333 (374/112402) while in subpopulation SAS AF= 0.00655 (18/2748). AF 95% confidence interval is 0.00466. There are 0 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 113 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC1A	NM_006306.4	c.*4952_*4953del		3_prime_UTR_variant	25/25	ENST00000322213.9
SMC1A	NM_001281463.1	c.*4952_*4953del		3_prime_UTR_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC1A	ENST00000322213.9	c.*4952_*4953del		3_prime_UTR_variant	25/25	1	NM_006306.4	P1
SMC1A	ENST00000375340.10	c.*4952_*4953del		3_prime_UTR_variant	26/26	1
SMC1A	ENST00000675504.1	c.*4952_*4953del		3_prime_UTR_variant	25/25

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 374 AN: 112349 Hom.: 0 Cov.: 23 AF XY: 0.00327 AC XY: 113 AN XY: 34509

Gnomad AFR AF: 0.000388

Gnomad AMI AF: 0.0117

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00653

Gnomad FIN AF: 0.00391

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00516

Gnomad OTH AF: 0.00132

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 48 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 24

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00333 AC: 374 AN: 112402 Hom.: 0 Cov.: 23 AF XY: 0.00327 AC XY: 113 AN XY: 34572

Gnomad4 AFR AF: 0.000388

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.00189

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00655

Gnomad4 FIN AF: 0.00391

Gnomad4 NFE AF: 0.00516

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.00578 Hom.: 28

Bravo AF: 0.00285

Asia WGS AF: 0.00358 AC: 9 AN: 2522

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

- -

Computational scores

Source: dbNSFP v4.3

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: rs782700101; hg19: chrX-53402070; COSMIC: COSV59128817;