chr19-18868665-CAAAG-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong
The NM_001492.6(GDF1):c.1047_1050delCTTT(p.Phe349LeufsTer35) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000953 in 1,574,596 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001492.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GDF1 | NM_001492.6 | c.1047_1050delCTTT | p.Phe349LeufsTer35 | frameshift_variant | Exon 8 of 8 | ENST00000247005.8 | NP_001483.3 | |
CERS1 | NM_021267.5 | c.*1316_*1319delCTTT | 3_prime_UTR_variant | Exon 8 of 8 | ENST00000623882.4 | NP_067090.1 | ||
GDF1 | NM_001387438.1 | c.1047_1050delCTTT | p.Phe349LeufsTer35 | frameshift_variant | Exon 5 of 5 | NP_001374367.1 | ||
CERS1 | NM_001387440.1 | c.*1908_*1911delCTTT | 3_prime_UTR_variant | Exon 7 of 7 | NP_001374369.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GDF1 | ENST00000247005.8 | c.1047_1050delCTTT | p.Phe349LeufsTer35 | frameshift_variant | Exon 8 of 8 | 1 | NM_001492.6 | ENSP00000247005.5 | ||
CERS1 | ENST00000623882 | c.*1316_*1319delCTTT | 3_prime_UTR_variant | Exon 8 of 8 | 1 | NM_021267.5 | ENSP00000485308.1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152088Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000651 AC: 12AN: 184466Hom.: 0 AF XY: 0.0000502 AC XY: 5AN XY: 99680
GnomAD4 exome AF: 0.000101 AC: 143AN: 1422508Hom.: 0 AF XY: 0.000101 AC XY: 71AN XY: 703908
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152088Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74300
ClinVar
Submissions by phenotype
not provided Pathogenic:3
This sequence change creates a premature translational stop signal (p.Phe349Leufs*35) in the GDF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the GDF1 protein. This variant is present in population databases (rs768027510, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with heterotaxy (internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 410641). For these reasons, this variant has been classified as Pathogenic. -
The c.1047_1050delCTTT variant in the GDF1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1047_1050delCTTT variant causes a frameshift starting with codon Phenylalanine 349, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 35 of the new reading frame, denoted p.Phe349LeufsX35. This frameshift variant replaces the typical last 24 amino acid residues in the GDF1 protein with 34 different amino acid residues, which is predicted to cause loss of normal protein function. The c.1047_1050delCTTT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1047_1050delCTTT as a likely pathogenic variant. -
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Congenital heart defects, multiple types, 6 Pathogenic:2
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with right atrial isomerism (MIM#208530). Although loss of function has been demonstrated for missense variants, there is currently limited evidence demonstrating loss of function for truncating variants (PMIDs: 1792434; 20413652). (I) 0106 - This gene is associated with autosomal recessive disease. This gene has been associated right atrial isomerism (Ivemark) (RAI) (MIM#208530) and congenital heart defects, multiple types, 6 (MIM#613854) (OMIM; PMID: 28991257). (I) 0208 - Variant is predicted to result in an elongated protein. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated TGF-beta like domain (NCBI conserved domain). (I) 0705 - No comparable protein truncating variants have previous evidence for pathogenicity. (I) 0803 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in 3 unrelated individuals from clinical testing laboratories (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual's fetus. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.681C>A; p.(Cys227*)) in a recessive disease (reported by Invitae #RQ1502139). (SP) 1205 - This variant has been shown to be maternally inherited in her fetus with symptoms consistent with congenital heart defects or heterotaxy (reported by Invitae #RQ1502139). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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Congenital heart defects, multiple types, 6;C3178806:Right atrial isomerism Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at