rs786204846

Variant names:

• chr4-118728586-T-G
• rs786204846
• NM_014822.4:c.2933A>C

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Cole-Carpenter syndrome 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• Cole-Carpenter syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 189341.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC24D	NM_014822.4	c.2933A>C	p.Gln978Pro	missense_variant	Exon 22 of 23	ENST00000280551.11	NP_055637.2
SEC24D	NM_001318066.2	c.2936A>C	p.Gln979Pro	missense_variant	Exon 22 of 23		NP_001304995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC24D	ENST00000280551.11	c.2933A>C	p.Gln978Pro	missense_variant	Exon 22 of 23	1	NM_014822.4	ENSP00000280551.6
SEC24D	ENST00000511481.5	c.1826A>C	p.Gln609Pro	missense_variant	Exon 15 of 16	1		ENSP00000425491.1
SEC24D	ENST00000502830.1	n.262A>C		non_coding_transcript_exon_variant	Exon 1 of 2	2
SEC24D	ENST00000505134.5	n.3064A>C		non_coding_transcript_exon_variant	Exon 17 of 18	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000809 AC: 2 AN: 247294 AF XY: 0.0000150

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000301 AC: 1 AN: 33234

American (AMR) AF: 0.00 AC: 0 AN: 43796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 84680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107312

Other (OTH) AF: 0.00 AC: 0 AN: 60100

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000945577), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

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

Mar 05, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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;.
PhyloP100		1.9
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
Mutation Taster		=28/72	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786204846; hg19: chr4-119649741;