chr4-118723632-T-G

Variant names:

• chr4-118723632-T-G
• NM_014822.4:c.2982A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014822.4(SEC24D):​c.2982A>C​(p.Glu994Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEC24D NM_014822.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.544

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029401451).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC24D	NM_014822.4	c.2982A>C	p.Glu994Asp	missense_variant	Exon 23 of 23	ENST00000280551.11	NP_055637.2
SEC24D	NM_001318066.2	c.2985A>C	p.Glu995Asp	missense_variant	Exon 23 of 23		NP_001304995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC24D	ENST00000280551.11	c.2982A>C	p.Glu994Asp	missense_variant	Exon 23 of 23	1	NM_014822.4	ENSP00000280551.6
SEC24D	ENST00000511481.5	c.1875A>C	p.Glu625Asp	missense_variant	Exon 16 of 16	1		ENSP00000425491.1
SEC24D	ENST00000502830.1	n.311A>C		non_coding_transcript_exon_variant	Exon 2 of 2	2
SEC24D	ENST00000505134.5	n.3113A>C		non_coding_transcript_exon_variant	Exon 18 of 18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2982A>C (p.E994D) alteration is located in exon 23 (coding exon 22) of the SEC24D gene. This alteration results from a A to C substitution at nucleotide position 2982, causing the glutamic acid (E) at amino acid position 994 to be replaced by an aspartic acid (D). 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	0.10
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.43
DANN	Benign	0.058
DEOGEN2	Benign	0.0058	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.65	N;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	2.2	N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.082
MutPred		0.37		Loss of glycosylation at P996 (P = 0.0433);.;
MVP		0.16
MPC		0.15
ClinPred		0.050	T
GERP RS		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-119644787;