rs782697006

Variant names:

• chrX-53411825-T-A
• rs782697006
• NM_006306.4:c.1190A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-53411825-T-A
• chrX-53411825-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_006306.4(SMC1A):​c.1190A>T​(p.Asn397Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,098,038 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: SMC1A NM_006306.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMC1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 68 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 6.4479 (above the threshold of 3.09). GenCC associations: The gene is linked to Cornelia de Lange syndrome, X-linked complex neurodevelopmental disorder, atypical Rett syndrome, Cornelia de Lange syndrome 2, developmental and epileptic encephalopathy, 85, with or without midline brain defects.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMC1A	NM_006306.4	c.1190A>T	p.Asn397Ile	missense_variant	Exon 7 of 25	ENST00000322213.9	NP_006297.2
SMC1A	NM_001281463.1	c.1124A>T	p.Asn375Ile	missense_variant	Exon 8 of 26		NP_001268392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMC1A	ENST00000322213.9	c.1190A>T	p.Asn397Ile	missense_variant	Exon 7 of 25	1	NM_006306.4	ENSP00000323421.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098038 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363394

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000119

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.6	L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.6	D;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0090	D;.
Sift4G	Benign	0.084	T;T
Polyphen		0.93	P;.
Vest4		0.78
MutPred		0.42		Loss of ubiquitination at K395 (P = 0.0828);.;
MVP		0.87
MPC		2.1
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.86
gMVP		0.86

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

Other links and lift over

dbSNP: rs782697006; hg19: chrX-53438775;