dbSNP rs770076998: TLNRD1:p.Ala127Asp (chr15-81002651-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_022566.3(TLNRD1):c.380C>A(p.Ala127Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000756 in 1,321,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A127V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

TLNRD1
NM_022566.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.94

Publications

0 publications found

Variant links:

Genes affected

TLNRD1 (HGNC:13519): (talin rod domain containing 1) This gene encodes a protein that is regulated by micro RNA MiR-574-3, and is thought to have an oncogenic function in human bladder cancer. A similar gene in mouse is located in a chromosomal region critical for differentiation of mesoderm, which affects embryo patterning and the formation of heart, muscle, blood, skeleton and the urogenital system. The mouse gene is expressed in early development, and in the adult. [provided by RefSeq, Nov 2016]

TLNRD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLNRD1	NM_022566.3 link	c.380C>A	p.Ala127Asp	missense_variant	Exon 1 of 1	ENST00000267984.4	NP_072088.1	Q9H1K6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLNRD1	ENST00000267984.4 link	c.380C>A	p.Ala127Asp	missense_variant	Exon 1 of 1	6	NM_022566.3	ENSP00000267984.2		Q9H1K6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.56e-7

AC:

AN:

1321994

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

649114

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26824

American (AMR)

AF:

0.00

AC:

AN:

23162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19268

East Asian (EAS)

AF:

0.00

AC:

AN:

34904

South Asian (SAS)

AF:

0.00

AC:

AN:

67760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5262

European-Non Finnish (NFE)

AF:

9.46e-7

AC:

AN:

1057150

Other (OTH)

AF:

0.00

AC:

AN:

54866

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.099

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-1.1

PhyloP100

6.9

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.81

MutPred

0.46

Gain of relative solvent accessibility (P = 0.09);

MVP

0.66

MPC

2.3

ClinPred

1.0

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.96

gMVP

0.89

Mutation Taster

=17/83

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over