8-96145564-G-C

Variant names:

• chr8-96145564-G-C
• rs11783820
• NM_001001557.4:c.407-40C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001001557.4(GDF6):​c.407-40C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 1,596,576 control chromosomes in the GnomAD database, including 1,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (141 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1757 hom.)
• Consequence: GDF6 NM_001001557.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.105
• Publications: 3 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 8-96145564-G-C is Benign according to our data. Variant chr8-96145564-G-C is described in ClinVar as Benign. ClinVar VariationId is 256850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF6	NM_001001557.4	c.407-40C>G		intron_variant	Intron 1 of 1	ENST00000287020.7	NP_001001557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF6	ENST00000287020.7	c.407-40C>G		intron_variant	Intron 1 of 1	1	NM_001001557.4	ENSP00000287020.4

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6032 AN: 152208 Hom.: 141 Cov.: 32

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.0595

Gnomad AMR AF: 0.0449

Gnomad ASJ AF: 0.0654

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0821

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0443

Gnomad OTH AF: 0.0550

GnomAD2 exomes AF: 0.0433 AC: 9885 AN: 228108 AF XY: 0.0470

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.0250

Gnomad ASJ exome AF: 0.0664

Gnomad EAS exome AF: 0.000286

Gnomad FIN exome AF: 0.0286

Gnomad NFE exome AF: 0.0453

Gnomad OTH exome AF: 0.0509

GnomAD4 exome AF: 0.0454 AC: 65554 AN: 1444252 Hom.: 1757 Cov.: 31 AF XY: 0.0471 AC XY: 33825 AN XY: 718814

African (AFR) AF: 0.0312 AC: 1042 AN: 33436

American (AMR) AF: 0.0272 AC: 1213 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 1752 AN: 26094

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39670

South Asian (SAS) AF: 0.0881 AC: 7545 AN: 85644

European-Finnish (FIN) AF: 0.0307 AC: 1155 AN: 37606

Middle Eastern (MID) AF: 0.149 AC: 854 AN: 5728

European-Non Finnish (NFE) AF: 0.0442 AC: 49105 AN: 1111194

Other (OTH) AF: 0.0478 AC: 2877 AN: 60218

GnomAD4 genome AF: 0.0396 AC: 6034 AN: 152324 Hom.: 141 Cov.: 32 AF XY: 0.0396 AC XY: 2950 AN XY: 74486

African (AFR) AF: 0.0296 AC: 1230 AN: 41584

American (AMR) AF: 0.0449 AC: 687 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 227 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.0828 AC: 400 AN: 4830

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10624

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0443 AC: 3015 AN: 68020

Other (OTH) AF: 0.0535 AC: 113 AN: 2114

Alfa AF: 0.0297 Hom.: 16

Bravo AF: 0.0388

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

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	-0.58
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11783820; hg19: chr8-97157792;