dbSNP rs758384905: TMEM106A:p.Ser34Cys (chr17-43213142-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145041.4(TMEM106A):c.101C>G(p.Ser34Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMEM106A
NM_145041.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.103

Publications

0 publications found

Variant links:

Genes affected

TMEM106A (HGNC:28288): (transmembrane protein 106A) Predicted to be involved in several processes, including glycoprotein biosynthetic process; positive regulation of cytokine production; and positive regulation of intracellular signal transduction. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM106A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11069614).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM106A	NM_145041.4 link	c.101C>G	p.Ser34Cys	missense_variant	Exon 3 of 9	ENST00000612339.4	NP_659478.1	Q96A25-1
TMEM106A	NM_001291586.2 link	c.101C>G	p.Ser34Cys	missense_variant	Exon 3 of 9		NP_001278515.1	Q96A25-1
TMEM106A	NM_001291588.2 link	c.101C>G	p.Ser34Cys	missense_variant	Exon 2 of 7		NP_001278517.1	B7Z779
TMEM106A	NM_001291587.2 link	c.5-48C>G		intron_variant	Intron 3 of 9		NP_001278516.1	Q96A25-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM106A	ENST00000612339.4 link	c.101C>G	p.Ser34Cys	missense_variant	Exon 3 of 9	2	NM_145041.4	ENSP00000483246.1		Q96A25-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251494

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 16, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.101C>G (p.S34C) alteration is located in exon 3 (coding exon 1) of the TMEM106A gene. This alteration results from a C to G substitution at nucleotide position 101, causing the serine (S) at amino acid position 34 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.018

T;T;T;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.68

T;.;T;T

M_CAP

Benign

0.0071

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

.;M;.;M

PhyloP100

0.10

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.98

.;.;N;.

REVEL

Benign

0.12

Sift

Benign

0.19

.;.;T;.

Sift4G

Benign

0.085

T;T;T;T

Polyphen

0.98, 0.99

.;D;D;D

Vest4

0.19, 0.23

MutPred

0.56

Loss of glycosylation at S34 (P = 0.0235);Loss of glycosylation at S34 (P = 0.0235);Loss of glycosylation at S34 (P = 0.0235);Loss of glycosylation at S34 (P = 0.0235);

MVP

0.030

ClinPred

0.25

GERP RS

2.9

Varity_R

0.068

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over