rs4834703

Variant names:

• chr4-118770469-G-A
• rs4834703
• NM_014822.4:c.1042-2158C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014822.4(SEC24D):​c.1042-2158C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.077 in 152,242 control chromosomes in the GnomAD database, including 552 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.077 (552 hom., cov: 32)
• Consequence: SEC24D NM_014822.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74
• Publications: 4 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0964 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014822.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC24D	NM_014822.4	MANE Select	c.1042-2158C>T		intron	N/A	NP_055637.2	O94855-1
	SEC24D	NM_001318066.2		c.1045-2158C>T		intron	N/A	NP_001304995.1	O94855-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC24D	ENST00000280551.11	TSL:1 MANE Select	c.1042-2158C>T		intron	N/A	ENSP00000280551.6	O94855-1
	SEC24D	ENST00000509818.5	TSL:1	n.*257-2158C>T		intron	N/A	ENSP00000424085.1	D6RBM1
	SEC24D	ENST00000514561.5	TSL:1	n.*1016-2158C>T		intron	N/A	ENSP00000422717.1	D6RAE2

Frequencies

GnomAD3 genomes AF: 0.0771 AC: 11729 AN: 152124 Hom.: 553 Cov.: 32

Gnomad AFR AF: 0.0398

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0857

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0439

Gnomad SAS AF: 0.0829

Gnomad FIN AF: 0.0690

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0983

Gnomad OTH AF: 0.0904

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0770 AC: 11720 AN: 152242 Hom.: 552 Cov.: 32 AF XY: 0.0758 AC XY: 5647 AN XY: 74458

African (AFR) AF: 0.0396 AC: 1647 AN: 41570

American (AMR) AF: 0.0854 AC: 1306 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 364 AN: 3470

East Asian (EAS) AF: 0.0438 AC: 227 AN: 5186

South Asian (SAS) AF: 0.0825 AC: 398 AN: 4822

European-Finnish (FIN) AF: 0.0690 AC: 732 AN: 10610

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0983 AC: 6687 AN: 67994

Other (OTH) AF: 0.0900 AC: 190 AN: 2112

Alfa AF: 0.0955 Hom.: 1679

Bravo AF: 0.0780

Asia WGS AF: 0.0660 AC: 229 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.8
DANN	Benign	0.62
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4834703; hg19: chr4-119691624;