chr19-18868664-T-TCAAAGAAGAGCA

Position:

• chr19-18868664-T-TCAAAGAAGAGCA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4

The NM_001492.6(GDF1):​c.1040_1051dupTGCTCTTCTTTG​(p.Val347_Phe350dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.00000141 in 1,423,136 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GDF1 NM_001492.6 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

Genes affected

GDF1 (HGNC:4214): (growth differentiation factor 1) 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. Studies in rodents suggest that this protein is involved in the establishment of left-right asymmetry in early embryogenesis and in neural development in later embryogenesis. The encoded protein is translated from a bicistronic mRNA that also encodes ceramide synthase 1. Mutations in this gene are associated with several congenital cardiovascular malformations. [provided by RefSeq, Jul 2016]

CERS1 (HGNC:14253): (ceramide synthase 1) This gene encodes a ceramide synthase enzyme, which catalyzes the synthesis of ceramide, the hydrophobic moiety of sphingolipids. The encoded enzyme synthesizes 18-carbon (C18) ceramide in brain neurons. Elevated expression of this gene may be associated with increased longevity, while decreased expression of this gene may be associated with myoclonus epilepsy with dementia in human patients. This protein is transcribed from a monocistronic mRNA as well as a bicistronic mRNA, which also encodes growth differentiation factor 1. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Embryonic growth/differentiation factor 1 (size 118) in uniprot entity GDF1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001492.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001492.6.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF1	NM_001492.6	c.1040_1051dupTGCTCTTCTTTG	p.Val347_Phe350dup	conservative_inframe_insertion	8/8	ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5	c.*1309_*1320dupTGCTCTTCTTTG		3_prime_UTR_variant	8/8	ENST00000623882.4	NP_067090.1
GDF1	NM_001387438.1	c.1040_1051dupTGCTCTTCTTTG	p.Val347_Phe350dup	conservative_inframe_insertion	5/5		NP_001374367.1
CERS1	NM_001387440.1	c.*1901_*1912dupTGCTCTTCTTTG		3_prime_UTR_variant	7/7		NP_001374369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8	c.1040_1051dupTGCTCTTCTTTG	p.Val347_Phe350dup	conservative_inframe_insertion	8/8	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000623882	c.*1309_*1320dupTGCTCTTCTTTG		3_prime_UTR_variant	8/8	1	NM_021267.5	ENSP00000485308.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000538 AC: 1 AN: 185902 Hom.: 0 AF XY: 0.00000995 AC XY: 1 AN XY: 100486

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1423136 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 704262

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 11, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with GDF1-related conditions. This variant is not present in population databases (ExAC no frequency). This variant, c.1040_1051dup, results in the insertion of 4 amino acid(s) to the GDF1 protein (p.Val347_Phe350dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1568289321; hg19: chr19-18979473;