rs148325203

Variant names:

• chr1-11022507-C-G
• rs148325203
• NM_007375.4:c.1098C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-11022507-C-G
• chr1-11022507-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007375.4(TARDBP):​c.1098C>G​(p.Ala366Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000492 in 1,597,750 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (4 hom.)
• Consequence: TARDBP NM_007375.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.586
• Publications: 7 publications found

Genes affected

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]

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]

MASP2 Gene-Disease associations (from GenCC):

• immunodeficiency due to MASP-2 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-11022507-C-G is Benign according to our data. Variant chr1-11022507-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 291740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.586 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000368 (56/152272) while in subpopulation EAS AF = 0.0102 (53/5192). AF 95% confidence interval is 0.00802. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 56 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007375.4. 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
	TARDBP	NM_007375.4	MANE Select	c.1098C>G	p.Ala366Ala	synonymous	Exon 6 of 6	NP_031401.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TARDBP	ENST00000240185.8	TSL:1 MANE Select	c.1098C>G	p.Ala366Ala	synonymous	Exon 6 of 6	ENSP00000240185.4
	TARDBP	ENST00000649624.1		c.768+330C>G		intron	N/A	ENSP00000497327.1
	TARDBP	ENST00000639083.1	TSL:5	c.1098C>G	p.Ala366Ala	synonymous	Exon 6 of 6	ENSP00000491203.1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000932 AC: 226 AN: 242534 AF XY: 0.000847

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.0000303

Gnomad ASJ exome AF: 0.000220

Gnomad EAS exome AF: 0.0118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.000505 AC: 730 AN: 1445478 Hom.: 4 Cov.: 31 AF XY: 0.000480 AC XY: 344 AN XY: 716574

African (AFR) AF: 0.00 AC: 0 AN: 33006

American (AMR) AF: 0.0000231 AC: 1 AN: 43328

Ashkenazi Jewish (ASJ) AF: 0.0000790 AC: 2 AN: 25324

East Asian (EAS) AF: 0.0174 AC: 686 AN: 39392

South Asian (SAS) AF: 0.0000588 AC: 5 AN: 84990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1101216

Other (OTH) AF: 0.000538 AC: 32 AN: 59532

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74440

African (AFR) AF: 0.00 AC: 0 AN: 41540

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0102 AC: 53 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000340

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Amyotrophic lateral sclerosis type 10 (1)
-	-	1	Amyotrophic lateral sclerosis type 10;C3150169:FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED (1)
-	-	1	Amyotrophic Lateral Sclerosis, Dominant (1)
-	-	1	Frontotemporal dementia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.1
DANN	Benign	0.80
PhyloP100		-0.59
PromoterAI		-0.045	Neutral
Mutation Taster		=98/2	polymorphism

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: rs148325203; hg19: chr1-11082564;