1-11016874-C-T

Variant names:

• chr1-11016874-C-T
• rs80356715
• NM_007375.4:c.269C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BS1_Supporting BS2

The NM_007375.4(TARDBP):​c.269C>T​(p.Ala90Val) variant causes a missense change. The variant allele was found at a frequency of 0.000416 in 1,614,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: TARDBP NM_007375.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1 O:1
• Conservation: PhyloP100: 5.89
• Publications: 74 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]

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: Likely_benign. The variant received -6 ACMG points.

• PP2: Missense variant in the TARDBP gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 3.7095 (above the threshold of 3.09). Trascript score misZ: 5.3115 (above the threshold of 3.09). GenCC associations: The gene is linked to amyotrophic lateral sclerosis type 10, frontotemporal dementia with motor neuron disease, amyotrophic lateral sclerosis, inclusion body myositis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13806838).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000263 (40/152320) while in subpopulation NFE AF = 0.000558 (38/68040). AF 95% confidence interval is 0.000418. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 40 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TARDBP	NM_007375.4	MANE Select	c.269C>T	p.Ala90Val	missense	Exon 3 of 6	NP_031401.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TARDBP	ENST00000240185.8	TSL:1 MANE Select	c.269C>T	p.Ala90Val	missense	Exon 3 of 6	ENSP00000240185.4
	TARDBP	ENST00000649624.1		c.269C>T	p.Ala90Val	missense	Exon 2 of 6	ENSP00000497327.1
	TARDBP	ENST00000639083.1	TSL:5	c.269C>T	p.Ala90Val	missense	Exon 3 of 6	ENSP00000491203.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000558

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000219 AC: 55 AN: 251440 AF XY: 0.000206

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000432 AC: 631 AN: 1461846 Hom.: 1 Cov.: 32 AF XY: 0.000414 AC XY: 301 AN XY: 727222

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000541 AC: 602 AN: 1112002

Other (OTH) AF: 0.000265 AC: 16 AN: 60392

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74482

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000558 AC: 38 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000462 Hom.: 0

Bravo AF: 0.000321

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Amyotrophic lateral sclerosis type 10 (3)
-	2	-	not provided (2)
-	1	-	Amyotrophic lateral sclerosis type 10;C3150169:FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Parkinsonian disorder (1)
-	1	-	TARDBP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Benign	0.42
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.082
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.17
Sift	Benign	0.63	T
Sift4G	Benign	1.0	T
Polyphen		0.15	B
Vest4		0.33
MVP		0.62
MPC		1.4
ClinPred		0.086	T
GERP RS		5.4
PromoterAI		0.021	Neutral
Varity_R		0.30
gMVP		0.80
Mutation Taster		=43/57	disease causing

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: rs80356715; hg19: chr1-11076931;