NM_006306.4:c.2973+45G>A

Variant names:

• chrX-53394733-C-T
• rs73210414
• NM_006306.4:c.2973+45G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_006306.4(SMC1A):​c.2973+45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (10 hom., 408 hem., cov: 20)
  • Exomes 𝑓: 0.028 (616 hom. 3821 hem.)
  • Failed GnomAD Quality Control
• Consequence: SMC1A NM_006306.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.20
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-53394733-C-T is Benign according to our data. Variant chrX-53394733-C-T is described in ClinVar as Benign. ClinVar VariationId is 259962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2973+45G>A		intron	N/A	NP_006297.2
	SMC1A	NM_001281463.1		c.2907+45G>A		intron	N/A	NP_001268392.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC1A	ENST00000322213.9	TSL:1 MANE Select	c.2973+45G>A		intron	N/A	ENSP00000323421.3
	SMC1A	ENST00000375340.10	TSL:1	c.2907+45G>A		intron	N/A	ENSP00000364489.7
	SMC1A	ENST00000675504.1		c.2907+45G>A		intron	N/A	ENSP00000502524.1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 1417 AN: 105212 Hom.: 10 Cov.: 20

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00620

Gnomad ASJ AF: 0.00235

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000441

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0122

GnomAD2 exomes AF: 0.0200 AC: 2351 AN: 117285 AF XY: 0.0224

Gnomad AFR exome AF: 0.00273

Gnomad AMR exome AF: 0.00671

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0506

Gnomad NFE exome AF: 0.0343

Gnomad OTH exome AF: 0.0160

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0277 AC: 9574 AN: 345873 Hom.: 616 Cov.: 3 AF XY: 0.0364 AC XY: 3821 AN XY: 104947

African (AFR) AF: 0.00333 AC: 36 AN: 10812

American (AMR) AF: 0.00756 AC: 179 AN: 23675

Ashkenazi Jewish (ASJ) AF: 0.00645 AC: 75 AN: 11626

East Asian (EAS) AF: 0.00 AC: 0 AN: 20106

South Asian (SAS) AF: 0.00127 AC: 45 AN: 35363

European-Finnish (FIN) AF: 0.0496 AC: 1424 AN: 28717

Middle Eastern (MID) AF: 0.0212 AC: 28 AN: 1321

European-Non Finnish (NFE) AF: 0.0375 AC: 7349 AN: 195743

Other (OTH) AF: 0.0237 AC: 438 AN: 18510

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0135 AC: 1417 AN: 105249 Hom.: 10 Cov.: 20 AF XY: 0.0146 AC XY: 408 AN XY: 28009

African (AFR) AF: 0.00219 AC: 63 AN: 28732

American (AMR) AF: 0.00619 AC: 60 AN: 9696

Ashkenazi Jewish (ASJ) AF: 0.00235 AC: 6 AN: 2553

East Asian (EAS) AF: 0.00 AC: 0 AN: 3294

South Asian (SAS) AF: 0.000443 AC: 1 AN: 2259

European-Finnish (FIN) AF: 0.0360 AC: 191 AN: 5301

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 208

European-Non Finnish (NFE) AF: 0.0211 AC: 1079 AN: 51126

Other (OTH) AF: 0.0120 AC: 17 AN: 1416

Alfa AF: 0.0162 Hom.: 110

Bravo AF: 0.0105

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.41
DANN	Benign	0.85
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73210414; hg19: chrX-53421653;