Genetic Variant QTMAN:p.Ala435Thr (chr2-143947126-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001376312.2(QTMAN):c.1303G>A(p.Ala435Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A435V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

QTMAN
NM_001376312.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.149

Publications

0 publications found

Variant links:

Genes affected

QTMAN (HGNC:20887): (glycosyltransferase like domain containing 1) Predicted to enable glycosyltransferase activity. [provided by Alliance of Genome Resources, Apr 2022]

QTMAN Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

QTMAN links:

GTDC1-AS1 (HGNC:58227):

GTDC1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06711766).

BP6

Variant 2-143947126-C-T is Benign according to our data. Variant chr2-143947126-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3283035.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 35 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376312.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
QTMAN	NM_001376312.2	MANE Select	c.1303G>A	p.Ala435Thr	missense	Exon 12 of 12	NP_001363241.1	Q4AE62-1
QTMAN	NM_001376306.2		c.1450G>A	p.Ala484Thr	missense	Exon 13 of 13	NP_001363235.1
QTMAN	NM_001006636.5		c.1303G>A	p.Ala435Thr	missense	Exon 12 of 12	NP_001006637.1	Q4AE62-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GTDC1	ENST00000682281.1	MANE Select	c.1303G>A	p.Ala435Thr	missense	Exon 12 of 12	ENSP00000507713.1	Q4AE62-1
GTDC1	ENST00000409214.5	TSL:1	c.1303G>A	p.Ala435Thr	missense	Exon 12 of 12	ENSP00000386581.1	Q4AE62-1
GTDC1	ENST00000463875.6	TSL:1	c.916G>A	p.Ala306Thr	missense	Exon 10 of 10	ENSP00000437964.1	Q4AE62-6

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000240

AC:

AN:

249840

AF XY:

0.0000370

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000267

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1460020

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726518

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33430

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1110394

Other (OTH)

AF:

0.0000166

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

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

AF:

0.0000263

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41374

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000225

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.45

CADD

Benign

8.3

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0051

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.68

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.59

M_CAP

Benign

0.025

MetaRNN

Benign

0.067

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.69

PhyloP100

0.15

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.42

REVEL

Benign

0.021

Sift

Benign

0.50

Sift4G

Benign

0.46

Polyphen

0.021

Vest4

0.058

MutPred

0.39

Gain of relative solvent accessibility (P = 0.1259)

MVP

0.40

MPC

0.038

ClinPred

0.037

GERP RS

0.47

Varity_R

0.032

gMVP

0.26

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over