dbSNP rs2012025: GMDS:c.988-1769C>T (chr6-1626309-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001500.4(GMDS):c.988-1769C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 152,126 control chromosomes in the GnomAD database, including 26,029 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.56 ( 26029 hom., cov: 34)

Exomes 𝑓: 0.17 ( 0 hom. )

Consequence

GMDS
NM_001500.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.423

Publications

8 publications found

Variant links:

Genes affected

GMDS (HGNC:4369): (GDP-mannose 4,6-dehydratase) GDP-mannose 4,6-dehydratase (GMD; EC 4.2.1.47) catalyzes the conversion of GDP-mannose to GDP-4-keto-6-deoxymannose, the first step in the synthesis of GDP-fucose from GDP-mannose, using NADP+ as a cofactor. The second and third steps of the pathway are catalyzed by a single enzyme, GDP-keto-6-deoxymannose 3,5-epimerase, 4-reductase, designated FX in humans (MIM 137020).[supplied by OMIM, Aug 2009]

GMDS links:

ENSG00000297192 (HGNC:):

ENSG00000297192 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GMDS	NM_001500.4 link	c.988-1769C>T	intron_variant	Intron 9 of 10	ENST00000380815.5	NP_001491.1	O60547-1
GMDS	NM_001253846.2 link	c.898-1769C>T	intron_variant	Intron 9 of 10		NP_001240775.1	O60547-2
GMDS	XM_011514500.2 link	c.898-1769C>T	intron_variant	Intron 9 of 10		XP_011512802.1
GMDS	XM_017010752.2 link	c.727-1769C>T	intron_variant	Intron 6 of 7		XP_016866241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMDS	ENST00000380815.5 link	c.988-1769C>T		intron_variant	Intron 9 of 10	1	NM_001500.4	ENSP00000370194.4		O60547-1

Frequencies

GnomAD3 genomes

AF:

0.555

AC:

84412

AN:

152002

Hom.:

25986

Cov.:

show subpopulations

Gnomad AFR

AF:

0.839

Gnomad AMI

AF:

0.388

Gnomad AMR

AF:

0.576

Gnomad ASJ

AF:

0.438

Gnomad EAS

AF:

0.531

Gnomad SAS

AF:

0.411

Gnomad FIN

AF:

0.403

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.423

Gnomad OTH

AF:

0.546

GnomAD4 exome

AF:

0.167

AC:

AN:

Hom.:

AF XY:

0.250

AC XY:

AN XY:

show subpopulations

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

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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:

0.556

AC:

84514

AN:

152120

Hom.:

26029

Cov.:

AF XY:

0.555

AC XY:

41248

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.840

AC:

34847

AN:

41508

American (AMR)

AF:

0.576

AC:

8799

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.438

AC:

1520

AN:

3468

East Asian (EAS)

AF:

0.531

AC:

2747

AN:

5178

South Asian (SAS)

AF:

0.412

AC:

1984

AN:

4820

European-Finnish (FIN)

AF:

0.403

AC:

4249

AN:

10556

Middle Eastern (MID)

AF:

0.459

AC:

135

AN:

294

European-Non Finnish (NFE)

AF:

0.423

AC:

28729

AN:

67984

Other (OTH)

AF:

0.544

AC:

1150

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1753

3505

5258

7010

8763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

696

1392

2088

2784

3480

<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:

0.464

Hom.:

28707

Bravo

AF:

0.583

Asia WGS

AF:

0.488

AC:

1695

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

0.42

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over