rs77859767

Variant names:

• chr8-96145563-G-A
• rs77859767
• NM_001001557.4:c.407-39C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-96145563-G-A
• chr8-96145563-G-C
• chr8-96145563-G-T

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.407-39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,596,908 control chromosomes in the GnomAD database, including 1,674 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (877 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (797 hom.)
• Consequence: GDF6 NM_001001557.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.63
• Publications: 4 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=-0.52).
• BP6: Variant 8-96145563-G-A is Benign according to our data. Variant chr8-96145563-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001557.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF6	NM_001001557.4	MANE Select	c.407-39C>T		intron	N/A	NP_001001557.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF6	ENST00000287020.7	TSL:1 MANE Select	c.407-39C>T		intron	N/A	ENSP00000287020.4

Frequencies

GnomAD3 genomes AF: 0.0581 AC: 8837 AN: 152194 Hom.: 873 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000564

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.0473

GnomAD2 exomes AF: 0.0152 AC: 3468 AN: 228560 AF XY: 0.0120

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.000885

Gnomad OTH exome AF: 0.00895

GnomAD4 exome AF: 0.00697 AC: 10072 AN: 1444596 Hom.: 797 Cov.: 31 AF XY: 0.00629 AC XY: 4520 AN XY: 718998

African (AFR) AF: 0.210 AC: 7014 AN: 33432

American (AMR) AF: 0.0111 AC: 496 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 664 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.000490 AC: 42 AN: 85730

European-Finnish (FIN) AF: 0.000505 AC: 19 AN: 37620

Middle Eastern (MID) AF: 0.0146 AC: 84 AN: 5740

European-Non Finnish (NFE) AF: 0.000764 AC: 849 AN: 1111386

Other (OTH) AF: 0.0150 AC: 904 AN: 60238

GnomAD4 genome AF: 0.0582 AC: 8867 AN: 152312 Hom.: 877 Cov.: 32 AF XY: 0.0556 AC XY: 4139 AN XY: 74480

African (AFR) AF: 0.200 AC: 8310 AN: 41560

American (AMR) AF: 0.0187 AC: 287 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 89 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.000564 AC: 6 AN: 10632

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68020

Other (OTH) AF: 0.0468 AC: 99 AN: 2116

Alfa AF: 0.0134 Hom.: 53

Bravo AF: 0.0664

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.94
PhyloP100		1.6
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: rs77859767; hg19: chr8-97157791;