X-53375458-A-G

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.*4645T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00725 in 111,567 control chromosomes in the GnomAD database, including 3 homozygotes. There are 285 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 0.0073 (3 hom., 285 hem., cov: 22)
  • 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: -0.889

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=-0.88).
• BP6: Variant X-53375458-A-G is Benign according to our data. Variant chrX-53375458-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 368552.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00725 (809/111567) while in subpopulation SAS AF= 0.0235 (62/2633). AF 95% confidence interval is 0.0189. There are 3 homozygotes in gnomad4. There are 285 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC1A	NM_006306.4	c.*4645T>C		3_prime_UTR_variant	25/25	ENST00000322213.9
SMC1A	NM_001281463.1	c.*4645T>C		3_prime_UTR_variant	26/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC1A	ENST00000322213.9	c.*4645T>C		3_prime_UTR_variant	25/25	1	NM_006306.4	P1
SMC1A	ENST00000375340.10	c.*4645T>C		3_prime_UTR_variant	26/26	1
SMC1A	ENST00000675504.1	c.*4645T>C		3_prime_UTR_variant	25/25

Frequencies

GnomAD3 genomes AF: 0.00726 AC: 810 AN: 111516 Hom.: 3 Cov.: 22 AF XY: 0.00848 AC XY: 286 AN XY: 33732

Gnomad AFR AF: 0.00173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00361

Gnomad ASJ AF: 0.0223

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.00834

Gnomad OTH AF: 0.00662

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 3 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.00725 AC: 809 AN: 111567 Hom.: 3 Cov.: 22 AF XY: 0.00843 AC XY: 285 AN XY: 33793

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00361

Gnomad4 ASJ AF: 0.0223

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0235

Gnomad4 FIN AF: 0.0233

Gnomad4 NFE AF: 0.00834

Gnomad4 OTH AF: 0.00654

Alfa AF: 0.0104 Hom.: 58

Bravo AF: 0.00591

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	-0.88
Cadd	Benign	0.049
Dann	Benign	0.27

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: rs150365487; hg19: chrX-53402379;