1-11026660-A-G

Variant names:

• chr1-11026660-A-G
• rs1033638
• NM_006610.4:c.*225T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006610.4(MASP2):​c.*225T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 374,014 control chromosomes in the GnomAD database, including 115,170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (40391 hom., cov: 31)
  • Exomes 𝑓: 0.82 (74779 hom.)
• Consequence: MASP2 NM_006610.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.41
• Publications: 24 publications found

Genes affected

MASP2 (HGNC:6902): (MBL associated serine protease 2) This gene encodes a member of the peptidase S1 family of serine proteases. The encoded preproprotein is proteolytically processed to generate A and B chains that heterodimerize to form the mature protease. This protease cleaves complement components C2 and C4 in order to generate C3 convertase in the lectin pathway of the complement system. The encoded protease also plays a role in the coagulation cascade through cleavage of prothrombin to form thrombin. Myocardial infarction and acute stroke patients exhibit reduced serum concentrations of the encoded protein. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

TARDBP (HGNC:11571): (TAR DNA binding protein) HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator Tat is dependent on an RNA regulatory element (TAR) located downstream of the transcription initiation site. The protein encoded by this gene is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. In addition, this protein regulates alternate splicing of the CFTR gene. A similar pseudogene is present on chromosome 20. [provided by RefSeq, Jul 2008]

TARDBP Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• frontotemporal dementia with motor neuron disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• inclusion body myositis

  Inheritance: AD Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-11026660-A-G is Benign according to our data. Variant chr1-11026660-A-G is described in ClinVar as Benign. ClinVar VariationId is 291772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.842 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006610.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASP2	NM_006610.4	MANE Select	c.*225T>C		3_prime_UTR	Exon 11 of 11	NP_006601.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MASP2	ENST00000400897.8	TSL:1 MANE Select	c.*225T>C		3_prime_UTR	Exon 11 of 11	ENSP00000383690.3
	MASP2	ENST00000700089.1		n.*1284T>C		non_coding_transcript_exon	Exon 10 of 10	ENSP00000514788.1
	MASP2	ENST00000700090.1		n.*1559T>C		non_coding_transcript_exon	Exon 10 of 10	ENSP00000514789.1

Frequencies

GnomAD3 genomes AF: 0.704 AC: 106918 AN: 151852 Hom.: 40379 Cov.: 31

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.890

Gnomad AMR AF: 0.764

Gnomad ASJ AF: 0.725

Gnomad EAS AF: 0.863

Gnomad SAS AF: 0.794

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.746

GnomAD4 exome AF: 0.816 AC: 181112 AN: 222042 Hom.: 74779 Cov.: 3 AF XY: 0.817 AC XY: 91908 AN XY: 112504

African (AFR) AF: 0.392 AC: 2576 AN: 6568

American (AMR) AF: 0.796 AC: 5361 AN: 6738

Ashkenazi Jewish (ASJ) AF: 0.734 AC: 6165 AN: 8400

East Asian (EAS) AF: 0.875 AC: 17583 AN: 20092

South Asian (SAS) AF: 0.792 AC: 2198 AN: 2776

European-Finnish (FIN) AF: 0.831 AC: 15228 AN: 18320

Middle Eastern (MID) AF: 0.776 AC: 881 AN: 1136

European-Non Finnish (NFE) AF: 0.834 AC: 119293 AN: 143006

Other (OTH) AF: 0.788 AC: 11827 AN: 15006

GnomAD4 genome AF: 0.704 AC: 106967 AN: 151972 Hom.: 40391 Cov.: 31 AF XY: 0.706 AC XY: 52453 AN XY: 74278

African (AFR) AF: 0.403 AC: 16683 AN: 41402

American (AMR) AF: 0.764 AC: 11645 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.725 AC: 2516 AN: 3470

East Asian (EAS) AF: 0.863 AC: 4460 AN: 5170

South Asian (SAS) AF: 0.794 AC: 3821 AN: 4812

European-Finnish (FIN) AF: 0.826 AC: 8743 AN: 10582

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.831 AC: 56484 AN: 67982

Other (OTH) AF: 0.749 AC: 1576 AN: 2104

Alfa AF: 0.765 Hom.: 84938

Bravo AF: 0.688

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency due to MASP-2 deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Amyotrophic Lateral Sclerosis, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frontotemporal dementia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.085
DANN	Benign	0.57
PhyloP100		-1.4
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: rs1033638; hg19: chr1-11086717;