8-96144995-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001001557.4(GDF6):c.936G>C(p.Ser312Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 1,379,714 control chromosomes in the GnomAD database, including 1,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 82 hom., cov: 32)

Exomes 𝑓: 0.038 ( 965 hom. )

Consequence

GDF6
NM_001001557.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.18

Publications

3 publications found

Variant links:

Genes affected

GDF6 (HGNC:4221): (growth differentiation factor 6) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein is required for normal formation of some bones and joints in the limbs, skull, and axial skeleton. Mutations in this gene are associated with Klippel-Feil syndrome, microphthalmia, and Leber congenital amaurosis. [provided by RefSeq, Sep 2016]

GDF6 Gene-Disease associations (from GenCC):

Klippel-Feil syndrome 1, autosomal dominant
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
microphthalmia
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
multiple synostoses syndrome 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
isolated Klippel-Feil syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated microphthalmia 4
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis 17
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

GDF6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 8-96144995-C-G is Benign according to our data. Variant chr8-96144995-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.18 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0262 (3960/151126) while in subpopulation NFE AF = 0.0398 (2693/67712). AF 95% confidence interval is 0.0385. There are 82 homozygotes in GnomAd4. There are 1893 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3960 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF6	NM_001001557.4 link	c.936G>C	p.Ser312Ser	synonymous_variant	Exon 2 of 2	ENST00000287020.7	NP_001001557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF6	ENST00000287020.7 link	c.936G>C	p.Ser312Ser	synonymous_variant	Exon 2 of 2	1	NM_001001557.4	ENSP00000287020.4

Frequencies

GnomAD3 genomes

AF:

0.0262

AC:

3960

AN:

151018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00714

Gnomad AMI

AF:

0.162

Gnomad AMR

AF:

0.0274

Gnomad ASJ

AF:

0.0303

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00725

Gnomad FIN

AF:

0.0203

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0398

Gnomad OTH

AF:

0.0303

GnomAD2 exomes

AF:

0.0334

AC:

1837

AN:

54992

AF XY:

0.0297

show subpopulations

Gnomad AFR exome

AF:

0.0105

Gnomad AMR exome

AF:

0.0259

Gnomad ASJ exome

AF:

0.0329

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0237

Gnomad NFE exome

AF:

0.0542

Gnomad OTH exome

AF:

0.0463

GnomAD4 exome

AF:

0.0375

AC:

46106

AN:

1228588

Hom.:

965

Cov.:

AF XY:

0.0367

AC XY:

22059

AN XY:

600532

show subpopulations

African (AFR)

AF:

0.00599

AC:

149

AN:

24882

American (AMR)

AF:

0.0278

AC:

537

AN:

19316

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

617

AN:

19656

East Asian (EAS)

AF:

0.0000372

AC:

AN:

26896

South Asian (SAS)

AF:

0.00943

AC:

487

AN:

51638

European-Finnish (FIN)

AF:

0.0207

AC:

644

AN:

31174

Middle Eastern (MID)

AF:

0.0338

AC:

125

AN:

3700

European-Non Finnish (NFE)

AF:

0.0418

AC:

41834

AN:

1001274

Other (OTH)

AF:

0.0342

AC:

1712

AN:

50052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

2460

4920

7379

9839

12299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1616

3232

4848

6464

8080

<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:

0.0262

AC:

3960

AN:

151126

Hom.:

Cov.:

AF XY:

0.0256

AC XY:

1893

AN XY:

73898

show subpopulations

African (AFR)

AF:

0.00712

AC:

295

AN:

41420

American (AMR)

AF:

0.0273

AC:

414

AN:

15156

Ashkenazi Jewish (ASJ)

AF:

0.0303

AC:

105

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00725

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0203

AC:

205

AN:

10106

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0398

AC:

2693

AN:

67712

Other (OTH)

AF:

0.0300

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

211

422

633

844

1055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0301

Hom.:

Bravo

AF:

0.0266

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 14, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Klippel-Feil syndrome 1, autosomal dominant

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Klippel-Feil syndrome 1, autosomal dominant;C2751307:Isolated microphthalmia 4;C3150968:Microphthalmia, isolated, with coloboma 6;C3715164:Leber congenital amaurosis 17

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.5

(source)

DANN

Benign

0.56

PhyloP100

-2.2

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over