Menu
GeneBe

4-118723580-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014822.4(SEC24D):c.3034G>A(p.Gly1012Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,613,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1012A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

SEC24D
NM_014822.4 missense

Scores

13
4
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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, 0.82

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SEC24DNM_014822.4 linkuse as main transcriptc.3034G>A p.Gly1012Arg missense_variant 23/23 ENST00000280551.11
SEC24DNM_001318066.2 linkuse as main transcriptc.3037G>A p.Gly1013Arg missense_variant 23/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SEC24DENST00000280551.11 linkuse as main transcriptc.3034G>A p.Gly1012Arg missense_variant 23/231 NM_014822.4 P1O94855-1
SEC24DENST00000511481.5 linkuse as main transcriptc.1927G>A p.Gly643Arg missense_variant 16/161
SEC24DENST00000502830.1 linkuse as main transcriptn.363G>A non_coding_transcript_exon_variant 2/22
SEC24DENST00000505134.5 linkuse as main transcriptn.3165G>A non_coding_transcript_exon_variant 18/182

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152026
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251052
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135718
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000561
AC:
82
AN:
1461624
Hom.:
0
Cov.:
30
AF XY:
0.0000605
AC XY:
44
AN XY:
727118
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000585
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152144
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.0000330
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 19, 2022This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1012 of the SEC24D protein (p.Gly1012Arg). This variant is present in population databases (rs753623656, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SEC24D-related conditions. ClinVar contains an entry for this variant (Variation ID: 1444765). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.66
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.35
Cadd
Pathogenic
26
Dann
Pathogenic
1.0
DEOGEN2
Benign
0.16
T;.
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Uncertain
0.40
D
MutationAssessor
Pathogenic
3.3
M;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-5.9
D;D
REVEL
Pathogenic
0.68
Sift
Uncertain
0.0020
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.76
MutPred
0.46
Gain of solvent accessibility (P = 0.0097);.;
MVP
0.89
MPC
0.77
ClinPred
0.86
D
GERP RS
5.6
Varity_R
0.83
gMVP
0.64

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: rs753623656; hg19: chr4-119644735; API