chrX-53396297-T-C

Variant names:

• chrX-53396297-T-C
• rs782728089
• NM_006306.4:c.2792A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006306.4(SMC1A):​c.2792A>G​(p.Gln931Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,441 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: SMC1A NM_006306.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.21
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.186299).

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.2792A>G	p.Gln931Arg	missense	Exon 18 of 25	NP_006297.2
	SMC1A	NM_001281463.1		c.2726A>G	p.Gln909Arg	missense	Exon 19 of 26	NP_001268392.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC1A	ENST00000322213.9	TSL:1 MANE Select	c.2792A>G	p.Gln931Arg	missense	Exon 18 of 25	ENSP00000323421.3
	SMC1A	ENST00000375340.10	TSL:1	c.2726A>G	p.Gln909Arg	missense	Exon 19 of 26	ENSP00000364489.7
	SMC1A	ENST00000675504.1		c.2726A>G	p.Gln909Arg	missense	Exon 18 of 25	ENSP00000502524.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 183439 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000273 AC: 3 AN: 1097441 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362801

African (AFR) AF: 0.00 AC: 0 AN: 26389

American (AMR) AF: 0.0000852 AC: 3 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54131

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841418

Other (OTH) AF: 0.00 AC: 0 AN: 46066

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.050	N
PhyloP100		3.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.41
Sift	Benign	0.77	T
Sift4G	Benign	0.80	T
Polyphen		0.49	P
Vest4		0.30
MutPred		0.49		Gain of MoRF binding (P = 0.0137)
MVP		0.98
MPC		1.6
ClinPred		0.21	T
GERP RS		4.9
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.87
Mutation Taster		=50/50

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: rs782728089; hg19: chrX-53423217;