dbSNP rs148778658: RIBC1:c.-387A>G (chrX-53422841-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000329209.9(RIBC1):c.-169A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 346,181 control chromosomes in the GnomAD database, including 13 homozygotes. There are 310 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0079 ( 11 hom., 256 hem., cov: 24)

Exomes 𝑓: 0.00099 ( 2 hom. 54 hem. )

Consequence

RIBC1
ENST00000329209.9 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.62

Publications

0 publications found

Variant links:

Genes affected

RIBC1 (HGNC:26537): (RIB43A domain with coiled-coils 1)

RIBC1 links:

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant X-53422841-A-G is Benign according to our data. Variant chrX-53422841-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1209126.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00794 (895/112787) while in subpopulation AFR AF = 0.0273 (849/31109). AF 95% confidence interval is 0.0258. There are 11 homozygotes in GnomAd4. There are 256 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000329209.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SMC1A	NM_006306.4	MANE Select	c.-241T>C	upstream_gene	N/A	NP_006297.2
RIBC1	NM_001031745.5	MANE Select	c.-253A>G	upstream_gene	N/A	NP_001026915.1	Q8N443-1
SMC1A	NM_001281463.1		c.-453T>C	upstream_gene	N/A	NP_001268392.1	G8JLG1

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
RIBC1	ENST00000868183.1	c.-387A>G	5_prime_UTR	Exon 1 of 8	ENSP00000538242.1
RIBC1	ENST00000929473.1	c.-169A>G	5_prime_UTR	Exon 3 of 10	ENSP00000599532.1
RIBC1	ENST00000947944.1	c.-562A>G	5_prime_UTR	Exon 1 of 7	ENSP00000618003.1

Frequencies

GnomAD3 genomes

AF:

0.00796

AC:

897

AN:

112736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0274

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000939

Gnomad OTH

AF:

0.00986

GnomAD4 exome

AF:

0.000990

AC:

231

AN:

233394

Hom.:

Cov.:

AF XY:

0.000756

AC XY:

AN XY:

71436

show subpopulations

African (AFR)

AF:

0.0263

AC:

189

AN:

7179

American (AMR)

AF:

0.000880

AC:

AN:

12505

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6684

East Asian (EAS)

AF:

0.00

AC:

AN:

14340

South Asian (SAS)

AF:

0.0000366

AC:

AN:

27312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12885

Middle Eastern (MID)

AF:

0.00111

AC:

AN:

899

European-Non Finnish (NFE)

AF:

0.00000724

AC:

AN:

138108

Other (OTH)

AF:

0.00208

AC:

AN:

13482

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00794

AC:

895

AN:

112787

Hom.:

Cov.:

AF XY:

0.00732

AC XY:

256

AN XY:

34959

show subpopulations

African (AFR)

AF:

0.0273

AC:

849

AN:

31109

American (AMR)

AF:

0.00241

AC:

AN:

10779

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3560

South Asian (SAS)

AF:

0.00

AC:

AN:

2770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6231

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000939

AC:

AN:

53243

Other (OTH)

AF:

0.00975

AC:

AN:

1539

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

127

159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00577

Hom.:

Bravo

AF:

0.00923

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.0090

(source)

DANN

Benign

0.62

PhyloP100

-3.6

PromoterAI

0.17

Neutral

(source)

Splicing

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