1-11026660-A-G

Position:

• chr1-11026660-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MASP2	NM_006610.4	c.*225T>C		3_prime_UTR_variant	11/11	ENST00000400897.8	NP_006601.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MASP2	ENST00000400897	c.*225T>C		3_prime_UTR_variant	11/11	1	NM_006610.4	ENSP00000383690.3

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

Gnomad4 AFR exome AF: 0.392

Gnomad4 AMR exome AF: 0.796

Gnomad4 ASJ exome AF: 0.734

Gnomad4 EAS exome AF: 0.875

Gnomad4 SAS exome AF: 0.792

Gnomad4 FIN exome AF: 0.831

Gnomad4 NFE exome AF: 0.834

Gnomad4 OTH exome AF: 0.788

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

Gnomad4 AFR AF: 0.403

Gnomad4 AMR AF: 0.764

Gnomad4 ASJ AF: 0.725

Gnomad4 EAS AF: 0.863

Gnomad4 SAS AF: 0.794

Gnomad4 FIN AF: 0.826

Gnomad4 NFE AF: 0.831

Gnomad4 OTH AF: 0.749

Alfa AF: 0.803 Hom.: 61865

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Amyotrophic Lateral Sclerosis, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Frontotemporal dementia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.085
DANN	Benign	0.57

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: rs1033638; hg19: chr1-11086717;