dbSNP rs142611198: SMC1A:p.Ala1150Ala (chrX-53381075-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006306.4(SMC1A):c.3450C>T(p.Ala1150Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,205,088 control chromosomes in the GnomAD database, including 5 homozygotes. There are 651 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1150A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., 58 hem., cov: 22)

Exomes 𝑓: 0.0016 ( 3 hom. 593 hem. )

Consequence

SMC1A
NM_006306.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.326

Publications

2 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
developmental and epileptic encephalopathy, 85, with or without midline brain defects
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant X-53381075-G-A is Benign according to our data. Variant chrX-53381075-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.326 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00177 (196/110486) while in subpopulation AMR AF = 0.00585 (61/10428). AF 95% confidence interval is 0.00467. There are 2 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 196 AD,XL gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006306.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC1A	NM_006306.4	MANE Select	c.3450C>T	p.Ala1150Ala	synonymous	Exon 23 of 25	NP_006297.2
	SMC1A	NM_001281463.1		c.3384C>T	p.Ala1128Ala	synonymous	Exon 24 of 26	NP_001268392.1	G8JLG1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMC1A	ENST00000322213.9	TSL:1 MANE Select	c.3450C>T	p.Ala1150Ala	synonymous	Exon 23 of 25	ENSP00000323421.3	Q14683
SMC1A	ENST00000375340.10	TSL:1	c.3384C>T	p.Ala1128Ala	synonymous	Exon 24 of 26	ENSP00000364489.7	G8JLG1
SMC1A	ENST00000675504.1		c.3384C>T	p.Ala1128Ala	synonymous	Exon 23 of 25	ENSP00000502524.1	G8JLG1

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

196

AN:

110433

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000264

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00586

Gnomad ASJ

AF:

0.00456

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0126

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.00203

GnomAD2 exomes

AF:

0.00147

AC:

269

AN:

183171

AF XY:

0.00166

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.00187

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000250

Gnomad NFE exome

AF:

0.00191

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00161

AC:

1763

AN:

1094602

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

593

AN XY:

360050

show subpopulations

African (AFR)

AF:

0.000266

AC:

AN:

26335

American (AMR)

AF:

0.00190

AC:

AN:

35192

Ashkenazi Jewish (ASJ)

AF:

0.00207

AC:

AN:

19358

East Asian (EAS)

AF:

0.00

AC:

AN:

30191

South Asian (SAS)

AF:

0.00148

AC:

AN:

54034

European-Finnish (FIN)

AF:

0.000247

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00606

AC:

AN:

4124

European-Non Finnish (NFE)

AF:

0.00172

AC:

1440

AN:

838875

Other (OTH)

AF:

0.00204

AC:

AN:

45967

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.00177

AC:

196

AN:

110486

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

AN XY:

32680

show subpopulations

African (AFR)

AF:

0.000264

AC:

AN:

30331

American (AMR)

AF:

0.00585

AC:

AN:

10428

Ashkenazi Jewish (ASJ)

AF:

0.00456

AC:

AN:

2632

East Asian (EAS)

AF:

0.00

AC:

AN:

3478

South Asian (SAS)

AF:

0.00

AC:

AN:

2517

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6007

Middle Eastern (MID)

AF:

0.0138

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00207

AC:

109

AN:

52699

Other (OTH)

AF:

0.00200

AC:

AN:

1499

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00207

Hom.:

Bravo

AF:

0.00171

EpiCase

AF:

0.00294

EpiControl

AF:

0.00267

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

Congenital muscular hypertrophy-cerebral syndrome (2)

Congenital muscular hypertrophy-cerebral syndrome;C5393312:Developmental and epileptic encephalopathy, 85, with or without midline brain defects (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

6.7

(source)

DANN

Benign

0.63

PhyloP100

-0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=84/16

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over