rs2296805

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_018960.6(GNMT):c.206+47T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 1,456,542 control chromosomes in the GnomAD database, including 264,820 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.66 ( 35321 hom., cov: 33)

Exomes 𝑓: 0.59 ( 229499 hom. )

Consequence

GNMT
NM_018960.6 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.96

Publications

25 publications found

Variant links:

Genes affected

GNMT (HGNC:4415): (glycine N-methyltransferase) The protein encoded by this gene is an enzyme that catalyzes the conversion of S-adenosyl-L-methionine (along with glycine) to S-adenosyl-L-homocysteine and sarcosine. This protein is found in the cytoplasm and acts as a homotetramer. Defects in this gene are a cause of GNMT deficiency (hypermethioninemia). Alternative splicing results in multiple transcript variants. Naturally occurring readthrough transcription occurs between the upstream CNPY3 (canopy FGF signaling regulator 3) gene and this gene and is represented with GeneID:107080644. [provided by RefSeq, Jan 2016]

GNMT links:

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PEX6 Gene-Disease associations (from GenCC):

peroxisome biogenesis disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
peroxisome biogenesis disorder 4A (Zellweger)
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
peroxisome biogenesis disorder 4B
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Heimler syndrome 2
Inheritance: AR Classification: MODERATE Submitted by: G2P
autosomal recessive cerebellar ataxia-blindness-deafness syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Zellweger spectrum disorders
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PEX6 links:

CNPY3-GNMT (HGNC:):

CNPY3-GNMT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 6-42961020-T-G is Benign according to our data. Variant chr6-42961020-T-G is described in ClinVar as Benign. ClinVar VariationId is 1265698.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018960.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GNMT	NM_018960.6	MANE Select	c.206+47T>G	intron	N/A	NP_061833.1	Q14749
GNMT	NM_001318865.2		c.206+47T>G	intron	N/A	NP_001305794.1	A0A0S2Z5F2
CNPY3-GNMT	NM_001318857.2		c.152-1742T>G	intron	N/A	NP_001305786.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GNMT	ENST00000372808.4	TSL:1 MANE Select	c.206+47T>G	intron	N/A	ENSP00000361894.3	Q14749
PEX6	ENST00000970120.1		c.*1464A>C	3_prime_UTR	Exon 18 of 18	ENSP00000640179.1
GNMT	ENST00000858688.1		c.206+47T>G	intron	N/A	ENSP00000528747.1

Frequencies

GnomAD3 genomes

AF:

0.661

AC:

100590

AN:

152078

Hom.:

35265

Cov.:

show subpopulations

Gnomad AFR

AF:

0.911

Gnomad AMI

AF:

0.686

Gnomad AMR

AF:

0.586

Gnomad ASJ

AF:

0.511

Gnomad EAS

AF:

0.337

Gnomad SAS

AF:

0.643

Gnomad FIN

AF:

0.523

Gnomad MID

AF:

0.592

Gnomad NFE

AF:

0.582

Gnomad OTH

AF:

0.646

GnomAD2 exomes

AF:

0.574

AC:

67666

AN:

117892

AF XY:

0.578

show subpopulations

Gnomad AFR exome

AF:

0.924

Gnomad AMR exome

AF:

0.535

Gnomad ASJ exome

AF:

0.520

Gnomad EAS exome

AF:

0.343

Gnomad FIN exome

AF:

0.512

Gnomad NFE exome

AF:

0.583

Gnomad OTH exome

AF:

0.590

GnomAD4 exome

AF:

0.589

AC:

767795

AN:

1304346

Hom.:

229499

Cov.:

AF XY:

0.590

AC XY:

379411

AN XY:

642802

show subpopulations

African (AFR)

AF:

0.925

AC:

27473

AN:

29710

American (AMR)

AF:

0.550

AC:

18773

AN:

34106

Ashkenazi Jewish (ASJ)

AF:

0.515

AC:

12164

AN:

23600

East Asian (EAS)

AF:

0.360

AC:

12539

AN:

34828

South Asian (SAS)

AF:

0.652

AC:

49202

AN:

75514

European-Finnish (FIN)

AF:

0.507

AC:

16957

AN:

33430

Middle Eastern (MID)

AF:

0.632

AC:

2590

AN:

4100

European-Non Finnish (NFE)

AF:

0.587

AC:

595410

AN:

1014282

Other (OTH)

AF:

0.597

AC:

32687

AN:

54776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

15872

31744

47616

63488

79360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16532

33064

49596

66128

82660

<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:

0.662

AC:

100709

AN:

152196

Hom.:

35321

Cov.:

AF XY:

0.655

AC XY:

48733

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.911

AC:

37877

AN:

41560

American (AMR)

AF:

0.586

AC:

8967

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.511

AC:

1773

AN:

3468

East Asian (EAS)

AF:

0.336

AC:

1737

AN:

5164

South Asian (SAS)

AF:

0.642

AC:

3100

AN:

4828

European-Finnish (FIN)

AF:

0.523

AC:

5548

AN:

10600

Middle Eastern (MID)

AF:

0.592

AC:

173

AN:

292

European-Non Finnish (NFE)

AF:

0.582

AC:

39539

AN:

67968

Other (OTH)

AF:

0.648

AC:

1372

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1623

3246

4870

6493

8116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

784

1568

2352

3136

3920

<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:

0.597

Hom.:

8011

Bravo

AF:

0.677

Asia WGS

AF:

0.544

AC:

1895

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

8.5

(source)

DANN

Benign

0.56

PhyloP100

2.0

PromoterAI

0.047

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over