4-118723562-C-T

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

Scores

10
3
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.57
Variant links:
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
SEC24DNM_014822.4 linkuse as main transcriptc.3052G>A p.Asp1018Asn missense_variant 23/23 ENST00000280551.11
SEC24DNM_001318066.2 linkuse as main transcriptc.3055G>A p.Asp1019Asn missense_variant 23/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SEC24DENST00000280551.11 linkuse as main transcriptc.3052G>A p.Asp1018Asn missense_variant 23/231 NM_014822.4 P1O94855-1
SEC24DENST00000511481.5 linkuse as main transcriptc.1945G>A p.Asp649Asn missense_variant 16/161
SEC24DENST00000502830.1 linkuse as main transcriptn.381G>A non_coding_transcript_exon_variant 2/22
SEC24DENST00000505134.5 linkuse as main transcriptn.3183G>A non_coding_transcript_exon_variant 18/182

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152064
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
250996
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135644
show subpopulations
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461596
Hom.:
0
Cov.:
30
AF XY:
0.00000825
AC XY:
6
AN XY:
727074
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000623
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1
Asia WGS
AF:
0.000289
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 04, 2023In 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 submitterclinical testingGeneDxJul 17, 2020Not 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.30
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.24
T;.
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.86
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Benign
0.058
D
MetaRNN
Pathogenic
0.78
D;D
MetaSVM
Benign
-0.49
T
MutationAssessor
Pathogenic
3.6
H;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-4.5
D;D
REVEL
Uncertain
0.38
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.93
MutPred
0.60
Gain of helix (P = 0.132);.;
MVP
0.62
MPC
0.69
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.73
gMVP
0.57

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs532948364; hg19: chr4-119644717; API