4-118723562-C-T
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_014822.4(SEC24D):c.3052G>A(p.Asp1018Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
SEC24D
NM_014822.4 missense
NM_014822.4 missense
Scores
10
3
6
Clinical Significance
Conservation
PhyloP100: 7.57
Genes affected
SEC24D (HGNC:10706): (SEC24 homolog D, COPII coat complex component) The protein encoded by this gene is a member of the SEC24 subfamily of the SEC23/SEC24 family, which is involved in vesicle trafficking. The encoded protein has similarity to yeast Sec24p component of COPII. COPII is the coat protein complex responsible for vesicle budding from the ER. This gene product is implicated in the shaping of the vesicle, and also in cargo selection and concentration. Mutations in this gene have been associated with Cole-Carpenter syndrome, a disorder affecting bone formation, resulting in craniofacial malformations and bones that break easily. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.776
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SEC24D | NM_014822.4 | c.3052G>A | p.Asp1018Asn | missense_variant | 23/23 | ENST00000280551.11 | |
SEC24D | NM_001318066.2 | c.3055G>A | p.Asp1019Asn | missense_variant | 23/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SEC24D | ENST00000280551.11 | c.3052G>A | p.Asp1018Asn | missense_variant | 23/23 | 1 | NM_014822.4 | P1 | |
SEC24D | ENST00000511481.5 | c.1945G>A | p.Asp649Asn | missense_variant | 16/16 | 1 | |||
SEC24D | ENST00000502830.1 | n.381G>A | non_coding_transcript_exon_variant | 2/2 | 2 | ||||
SEC24D | ENST00000505134.5 | n.3183G>A | non_coding_transcript_exon_variant | 18/18 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152064Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
3
AN:
152064
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250996Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135644
GnomAD3 exomes
AF:
AC:
1
AN:
250996
Hom.:
AF XY:
AC XY:
0
AN XY:
135644
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461596Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 727074
GnomAD4 exome
AF:
AC:
9
AN:
1461596
Hom.:
Cov.:
30
AF XY:
AC XY:
6
AN XY:
727074
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74412
GnomAD4 genome
AF:
AC:
3
AN:
152178
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
74412
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ExAC
AF:
AC:
1
Asia WGS
AF:
AC:
1
AN:
3478
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 04, 2023 | 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1196804). This variant has not been reported in the literature in individuals affected with SEC24D-related conditions. This variant is present in population databases (rs532948364, gnomAD 0.003%). This sequence change replaces aspartic acid with asparagine at codon 1018 of the SEC24D protein (p.Asp1018Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 17, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Gain of helix (P = 0.132);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at