rs147791932

Positions:

chrX-53412268-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.128

Variant links:

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 links:

SMC1A (HGNC:):

SMC1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 159964.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}. Variant chrX-53412268-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMC1A	NM_006306.4 linkuse as main transcript	c.855-15C>T		intron_variant		ENST00000322213.9	NP_006297.2	Q14683A0A384MR33Q68EN4
SMC1A	NM_001281463.1 linkuse as main transcript	c.789-15C>T		intron_variant			NP_001268392.1	G8JLG1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9 linkuse as main transcript	c.855-15C>T		intron_variant		1	NM_006306.4	ENSP00000323421.3		Q14683

Frequencies

GnomAD3 genomes

AF:

0.00307

AC:

343

AN:

111589

Hom.:

Cov.:

AF XY:

0.00296

AC XY:

100

AN XY:

33779

show subpopulations

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

GnomAD3 exomes

AF:

0.000740

AC:

135

AN:

182501

Hom.:

AF XY:

0.000476

AC XY:

AN XY:

67287

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000216

AC XY:

AN XY:

361298

show subpopulations

Gnomad4 AFR exome

AF:

0.0103

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000357

Gnomad4 OTH exome

AF:

0.000326

GnomAD4 genome

AF:

0.00307

AC:

343

AN:

111642

Hom.:

Cov.:

AF XY:

0.00295

AC XY:

100

AN XY:

33842

show subpopulations

Gnomad4 AFR

AF:

0.0110

Gnomad4 AMR

AF:

0.000383

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.000658

Alfa

AF:

0.00234

Hom.:

Bravo

AF:

0.00332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Congenital muscular hypertrophy-cerebral syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.89

DANN

Benign

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over