NM_001001557.4:c.406+28C>A

Variant names:

• chr8-96160259-G-T
• rs62516290
• NM_001001557.4:c.406+28C>A

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.406+28C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0785 in 1,612,804 control chromosomes in the GnomAD database, including 5,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (397 hom., cov: 33)
  • Exomes 𝑓: 0.080 (5314 hom.)
• Consequence: GDF6 NM_001001557.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.20
• Publications: 5 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=-0.78).
• BP6: Variant 8-96160259-G-T is Benign according to our data. Variant chr8-96160259-G-T is described in ClinVar as Benign. ClinVar VariationId is 256848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF6	NM_001001557.4	c.406+28C>A		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.406+28C>A		intron_variant	Intron 1 of 1	1	NM_001001557.4	ENSP00000287020.4

Frequencies

GnomAD3 genomes AF: 0.0633 AC: 9634 AN: 152200 Hom.: 396 Cov.: 33

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0696

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0487

Gnomad MID AF: 0.102

Gnomad NFE AF: 0.0936

Gnomad OTH AF: 0.0737

GnomAD2 exomes AF: 0.0624 AC: 15589 AN: 249932 AF XY: 0.0629

Gnomad AFR exome AF: 0.0262

Gnomad AMR exome AF: 0.0564

Gnomad ASJ exome AF: 0.0659

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0528

Gnomad NFE exome AF: 0.0923

Gnomad OTH exome AF: 0.0845

GnomAD4 exome AF: 0.0801 AC: 116965 AN: 1460486 Hom.: 5314 Cov.: 32 AF XY: 0.0787 AC XY: 57183 AN XY: 726708

African (AFR) AF: 0.0232 AC: 778 AN: 33468

American (AMR) AF: 0.0586 AC: 2619 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0627 AC: 1639 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0160 AC: 1381 AN: 86222

European-Finnish (FIN) AF: 0.0553 AC: 2954 AN: 53414

Middle Eastern (MID) AF: 0.0631 AC: 364 AN: 5766

European-Non Finnish (NFE) AF: 0.0926 AC: 102841 AN: 1110696

Other (OTH) AF: 0.0727 AC: 4388 AN: 60372

GnomAD4 genome AF: 0.0632 AC: 9633 AN: 152318 Hom.: 397 Cov.: 33 AF XY: 0.0601 AC XY: 4477 AN XY: 74480

African (AFR) AF: 0.0273 AC: 1135 AN: 41590

American (AMR) AF: 0.0695 AC: 1064 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 210 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4824

European-Finnish (FIN) AF: 0.0487 AC: 517 AN: 10618

Middle Eastern (MID) AF: 0.106 AC: 31 AN: 292

European-Non Finnish (NFE) AF: 0.0937 AC: 6370 AN: 68018

Other (OTH) AF: 0.0729 AC: 154 AN: 2112

Alfa AF: 0.0672 Hom.: 183

Bravo AF: 0.0647

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.78
CADD	Benign	8.9
DANN	Benign	0.78
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62516290; hg19: chr8-97172487;