rs786204846

chr4-118728586-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_014822.4(SEC24D):c.2933A>C(p.Gln978Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SEC24D NM_014822.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.87

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-118728586-T-G is Pathogenic according to our data. Variant chr4-118728586-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 189341.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC24D	NM_014822.4	c.2933A>C	p.Gln978Pro	missense_variant	22/23	ENST00000280551.11
SEC24D	NM_001318066.2	c.2936A>C	p.Gln979Pro	missense_variant	22/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC24D	ENST00000280551.11	c.2933A>C	p.Gln978Pro	missense_variant	22/23	1	NM_014822.4	P1
SEC24D	ENST00000511481.5	c.1826A>C	p.Gln609Pro	missense_variant	15/16	1
SEC24D	ENST00000502830.1	n.262A>C		non_coding_transcript_exon_variant	1/2	2
SEC24D	ENST00000505134.5	n.3064A>C		non_coding_transcript_exon_variant	17/18	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000809 AC: 2 AN: 247294 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133444

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453678 Hom.: 0 Cov.: 27 AF XY: 0.00000415 AC XY: 3 AN XY: 723236

Gnomad4 AFR exome AF: 0.0000301

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cole-Carpenter syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 05, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.52
Sift	Benign	0.043	D;T
Sift4G	Uncertain	0.023	D;T
Polyphen		0.91	P;.
Vest4		0.87
MutPred		0.48		Loss of glycosylation at P982 (P = 0.0251);.;
MVP		0.50
MPC		0.61
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.74

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

LitVar

Other links and lift over

dbSNP: rs786204846; hg19: chr4-119649741;