8-96144183-T-C

Variant names:

• chr8-96144183-T-C
• rs2440199
• NM_001001557.4:c.*380A>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.*380A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 223,256 control chromosomes in the GnomAD database, including 45,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33295 hom., cov: 25)
  • Exomes 𝑓: 0.53 (11828 hom.)
• Consequence: GDF6 NM_001001557.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.947
• Publications: 7 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=-0.91).
• BP6: Variant 8-96144183-T-C is Benign according to our data. Variant chr8-96144183-T-C is described in ClinVar as Benign. ClinVar VariationId is 364023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.869 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF6	NM_001001557.4	MANE Select	c.*380A>G		3_prime_UTR	Exon 2 of 2	NP_001001557.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF6	ENST00000287020.7	TSL:1 MANE Select	c.*380A>G		3_prime_UTR	Exon 2 of 2	ENSP00000287020.4

Frequencies

GnomAD3 genomes AF: 0.650 AC: 96667 AN: 148784 Hom.: 33242 Cov.: 25

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.682

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.626

GnomAD4 exome AF: 0.533 AC: 39650 AN: 74346 Hom.: 11828 Cov.: 0 AF XY: 0.534 AC XY: 21008 AN XY: 39324

African (AFR) AF: 0.862 AC: 1570 AN: 1822

American (AMR) AF: 0.379 AC: 1572 AN: 4150

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 1043 AN: 1764

East Asian (EAS) AF: 0.221 AC: 859 AN: 3888

South Asian (SAS) AF: 0.546 AC: 6034 AN: 11042

European-Finnish (FIN) AF: 0.499 AC: 1710 AN: 3424

Middle Eastern (MID) AF: 0.580 AC: 160 AN: 276

European-Non Finnish (NFE) AF: 0.557 AC: 24504 AN: 44032

Other (OTH) AF: 0.557 AC: 2198 AN: 3948

GnomAD4 genome AF: 0.650 AC: 96779 AN: 148910 Hom.: 33295 Cov.: 25 AF XY: 0.643 AC XY: 46531 AN XY: 72334

African (AFR) AF: 0.877 AC: 35423 AN: 40404

American (AMR) AF: 0.471 AC: 6957 AN: 14780

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2221 AN: 3458

East Asian (EAS) AF: 0.276 AC: 1367 AN: 4948

South Asian (SAS) AF: 0.591 AC: 2776 AN: 4696

European-Finnish (FIN) AF: 0.552 AC: 5438 AN: 9860

Middle Eastern (MID) AF: 0.695 AC: 196 AN: 282

European-Non Finnish (NFE) AF: 0.602 AC: 40632 AN: 67518

Other (OTH) AF: 0.629 AC: 1295 AN: 2060

Alfa AF: 0.631 Hom.: 3903

Bravo AF: 0.644

Asia WGS AF: 0.451 AC: 1566 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Klippel-Feil syndrome 1, autosomal dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.94
DANN	Benign	0.51
PhyloP100		-0.95
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: rs2440199; hg19: chr8-97156411;