Genetic Variant NM_018972.4:c.507T>G (chr8-74361906-T-G) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_018972.4(GDAP1):c.507T>G(p.Ser169Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 1,593,766 control chromosomes in the GnomAD database, including 78,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5924 hom., cov: 33)

Exomes 𝑓: 0.31 ( 72210 hom. )

Consequence

GDAP1
NM_018972.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:2B:11

Conservation

PhyloP100: -0.915

Publications

21 publications found

Variant links:

Genes affected

GDAP1 (HGNC:15968): (ganglioside induced differentiation associated protein 1) This gene encodes a member of the ganglioside-induced differentiation-associated protein family, which may play a role in a signal transduction pathway during neuronal development. Mutations in this gene have been associated with various forms of Charcot-Marie-Tooth Disease and neuropathy. Two transcript variants encoding different isoforms and a noncoding variant have been identified for this gene. [provided by RefSeq, Feb 2012]

GDAP1 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease axonal type 2K
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
Charcot-Marie-Tooth disease recessive intermediate A
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
autosomal dominant Charcot-Marie-Tooth disease type 2K
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 4A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GDAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 8-74361906-T-G is Benign according to our data. Variant chr8-74361906-T-G is described in ClinVar as Benign. ClinVar VariationId is 261065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.915 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018972.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GDAP1	NM_018972.4	MANE Select	c.507T>G	p.Ser169Ser	synonymous	Exon 4 of 6	NP_061845.2	Q8TB36-1
GDAP1	NM_001362930.2		c.333T>G	p.Ser111Ser	synonymous	Exon 3 of 5	NP_001349859.1	A0A6Q8PEZ4
GDAP1	NM_001040875.4		c.303T>G	p.Ser101Ser	synonymous	Exon 4 of 6	NP_001035808.1	Q8TB36-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GDAP1	ENST00000220822.12	TSL:1 MANE Select	c.507T>G	p.Ser169Ser	synonymous	Exon 4 of 6	ENSP00000220822.7	Q8TB36-1
GDAP1	ENST00000434412.3	TSL:1	c.375T>G	p.Ser125Ser	synonymous	Exon 5 of 7	ENSP00000417006.3	A0A7I2RYU0
GDAP1	ENST00000675463.1		c.507T>G	p.Ser169Ser	synonymous	Exon 4 of 7	ENSP00000502327.1	A0A6Q8PGS2

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39562

AN:

152060

Hom.:

5924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.118

Gnomad AMI

AF:

0.314

Gnomad AMR

AF:

0.241

Gnomad ASJ

AF:

0.307

Gnomad EAS

AF:

0.312

Gnomad SAS

AF:

0.210

Gnomad FIN

AF:

0.333

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.336

Gnomad OTH

AF:

0.279

GnomAD2 exomes

AF:

0.279

AC:

70092

AN:

251004

AF XY:

0.283

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.185

Gnomad ASJ exome

AF:

0.283

Gnomad EAS exome

AF:

0.323

Gnomad FIN exome

AF:

0.328

Gnomad NFE exome

AF:

0.332

Gnomad OTH exome

AF:

0.306

GnomAD4 exome

AF:

0.309

AC:

446116

AN:

1441588

Hom.:

72210

Cov.:

AF XY:

0.307

AC XY:

220652

AN XY:

718540

show subpopulations

African (AFR)

AF:

0.107

AC:

3554

AN:

33290

American (AMR)

AF:

0.194

AC:

8652

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.287

AC:

7459

AN:

25998

East Asian (EAS)

AF:

0.278

AC:

11023

AN:

39594

South Asian (SAS)

AF:

0.208

AC:

17845

AN:

85972

European-Finnish (FIN)

AF:

0.332

AC:

17631

AN:

53120

Middle Eastern (MID)

AF:

0.261

AC:

1501

AN:

5746

European-Non Finnish (NFE)

AF:

0.330

AC:

360866

AN:

1093386

Other (OTH)

AF:

0.294

AC:

17585

AN:

59778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

13408

26816

40225

53633

67041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11336

22672

34008

45344

56680

<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:

0.260

AC:

39579

AN:

152178

Hom.:

5924

Cov.:

AF XY:

0.260

AC XY:

19375

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.117

AC:

4875

AN:

41538

American (AMR)

AF:

0.241

AC:

3679

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

1063

AN:

3468

East Asian (EAS)

AF:

0.313

AC:

1615

AN:

5162

South Asian (SAS)

AF:

0.210

AC:

1015

AN:

4826

European-Finnish (FIN)

AF:

0.333

AC:

3520

AN:

10578

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.336

AC:

22854

AN:

67996

Other (OTH)

AF:

0.281

AC:

595

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1464

2928

4392

5856

7320

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<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:

0.284

Hom.:

4390

Bravo

AF:

0.246

Asia WGS

AF:

0.256

AC:

892

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (2)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth disease axonal type 2K (1)

Charcot-Marie-Tooth disease recessive intermediate A (1)

Charcot-Marie-Tooth disease type 4A (1)

Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

5.4

(source)

DANN

Benign

0.76

PhyloP100

-0.92

Mutation Taster

=94/6

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