Genetic Variant SEC24D:p.Val990Ile (chr4-118723646-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014822.4(SEC24D):c.2968G>A(p.Val990Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000187 in 1,600,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SEC24D
NM_014822.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.86

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]

SEC24D links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22147402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC24D	NM_014822.4 link	c.2968G>A	p.Val990Ile	missense_variant	Exon 23 of 23	ENST00000280551.11	NP_055637.2	O94855-1A8K6V0
SEC24D	NM_001318066.2 link	c.2971G>A	p.Val991Ile	missense_variant	Exon 23 of 23		NP_001304995.1	O94855-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SEC24D	ENST00000280551.11 link	c.2968G>A	p.Val990Ile	missense_variant	Exon 23 of 23	1	NM_014822.4	ENSP00000280551.6	O94855-1
SEC24D	ENST00000511481.5 link	c.1861G>A	p.Val621Ile	missense_variant	Exon 16 of 16	1		ENSP00000425491.1	E9PDM8
SEC24D	ENST00000502830.1 link	n.297G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
SEC24D	ENST00000505134.5 link	n.3099G>A		non_coding_transcript_exon_variant	Exon 18 of 18	2

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151456

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449378

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720498

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151456

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73902

show subpopulations

Gnomad4 AFR

AF:

0.0000243

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2968G>A (p.V990I) alteration is located in exon 23 (coding exon 22) of the SEC24D gene. This alteration results from a G to A substitution at nucleotide position 2968, causing the valine (V) at amino acid position 990 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.013

T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.063

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.78

N;N

REVEL

Benign

0.16

Sift

Benign

0.14

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.074

B;.

Vest4

0.18

MutPred

0.44

Loss of catalytic residue at V990 (P = 0.0578);.;

MVP

0.43

MPC

0.14

ClinPred

0.59

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.17

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over