X-53380089-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006306.4(SMC1A):c.*14C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00565 in 1,168,433 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,986 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 0.0043 ( 1 hom., 133 hem., cov: 22)

Exomes 𝑓: 0.0058 ( 9 hom. 1853 hem. )

Consequence

SMC1A
NM_006306.4 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.679

Publications

0 publications found

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 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

SMC1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant X-53380089-G-A is Benign according to our data. Variant chrX-53380089-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159937.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00434 (482/111102) while in subpopulation NFE AF = 0.00742 (393/52982). AF 95% confidence interval is 0.00681. There are 1 homozygotes in GnomAd4. There are 133 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 482 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC1A	NM_006306.4 link	c.*14C>T		3_prime_UTR_variant	Exon 25 of 25	ENST00000322213.9	NP_006297.2	Q14683A0A384MR33Q68EN4
SMC1A	NM_001281463.1 link	c.*14C>T		3_prime_UTR_variant	Exon 26 of 26		NP_001268392.1	G8JLG1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMC1A	ENST00000322213.9 link	c.*14C>T	3_prime_UTR_variant	Exon 25 of 25	1	NM_006306.4	ENSP00000323421.3	Q14683
SMC1A	ENST00000375340.10 link	c.*14C>T	3_prime_UTR_variant	Exon 26 of 26	1		ENSP00000364489.7	G8JLG1
SMC1A	ENST00000675504.1 link	c.*14C>T	3_prime_UTR_variant	Exon 25 of 25			ENSP00000502524.1	G8JLG1
SMC1A	ENST00000674590.1 link	c.*14C>T	3_prime_UTR_variant	Exon 23 of 23			ENSP00000502626.1	A0A6Q8PHC3

Frequencies

GnomAD3 genomes

AF:

0.00435

AC:

483

AN:

111049

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000886

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00279

Gnomad ASJ

AF:

0.00113

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000768

Gnomad FIN

AF:

0.00318

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.00742

Gnomad OTH

AF:

0.00534

GnomAD2 exomes

AF:

0.00429

AC:

767

AN:

178732

AF XY:

0.00436

show subpopulations

Gnomad AFR exome

AF:

0.000778

Gnomad AMR exome

AF:

0.00284

Gnomad ASJ exome

AF:

0.00111

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00241

Gnomad NFE exome

AF:

0.00735

Gnomad OTH exome

AF:

0.00527

GnomAD4 exome

AF:

0.00578

AC:

6116

AN:

1057331

Hom.:

Cov.:

AF XY:

0.00560

AC XY:

1853

AN XY:

330919

show subpopulations

African (AFR)

AF:

0.000780

AC:

AN:

25655

American (AMR)

AF:

0.00325

AC:

114

AN:

35093

Ashkenazi Jewish (ASJ)

AF:

0.000897

AC:

AN:

18951

East Asian (EAS)

AF:

0.00

AC:

AN:

30042

South Asian (SAS)

AF:

0.00154

AC:

AN:

52687

European-Finnish (FIN)

AF:

0.00408

AC:

165

AN:

40450

Middle Eastern (MID)

AF:

0.0140

AC:

AN:

3918

European-Non Finnish (NFE)

AF:

0.00671

AC:

5410

AN:

805789

Other (OTH)

AF:

0.00568

AC:

254

AN:

44746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

204

407

611

814

1018

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

186

372

558

744

930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00434

AC:

482

AN:

111102

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

133

AN XY:

33322

show subpopulations

African (AFR)

AF:

0.000884

AC:

AN:

30546

American (AMR)

AF:

0.00278

AC:

AN:

10414

Ashkenazi Jewish (ASJ)

AF:

0.00113

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3534

South Asian (SAS)

AF:

0.000770

AC:

AN:

2596

European-Finnish (FIN)

AF:

0.00318

AC:

AN:

5973

Middle Eastern (MID)

AF:

0.00461

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00742

AC:

393

AN:

52982

Other (OTH)

AF:

0.00528

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00463

Hom.:

Bravo

AF:

0.00452

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

History of neurodevelopmental disorder

Uncertain:1

Jan 10, 2013

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

There is insufficient or conflicting evidence for classification of this alteration. -

not specified

Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.7

(source)

DANN

Benign

0.70

PhyloP100

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over