4-118727244-A-G

Variant names:

• chr4-118727244-A-G
• rs298988
• NM_014822.4:c.2958+1317T>C

Variant summary

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

The NM_014822.4(SEC24D):​c.2958+1317T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.722 in 152,150 control chromosomes in the GnomAD database, including 40,445 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 0.72 (40445 hom., cov: 32)
• Consequence: SEC24D NM_014822.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.426
• 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: 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=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.779 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.2958+1317T>C		intron	N/A	NP_055637.2	O94855-1
	SEC24D	NM_001318066.2		c.2961+1317T>C		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.2958+1317T>C		intron	N/A	ENSP00000280551.6	O94855-1
	SEC24D	ENST00000511481.5	TSL:1	c.1851+1317T>C		intron	N/A	ENSP00000425491.1	E9PDM8
	SEC24D	ENST00000924655.1		c.2958+1317T>C		intron	N/A	ENSP00000594714.1

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109837 AN: 152032 Hom.: 40416 Cov.: 32

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.660

Gnomad AMR AF: 0.757

Gnomad ASJ AF: 0.824

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.792

Gnomad FIN AF: 0.820

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.785

Gnomad OTH AF: 0.736

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

GnomAD4 genome AF: 0.722 AC: 109924 AN: 152150 Hom.: 40445 Cov.: 32 AF XY: 0.727 AC XY: 54055 AN XY: 74378

African (AFR) AF: 0.560 AC: 23249 AN: 41482

American (AMR) AF: 0.757 AC: 11578 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 2861 AN: 3472

East Asian (EAS) AF: 0.773 AC: 4003 AN: 5180

South Asian (SAS) AF: 0.793 AC: 3824 AN: 4822

European-Finnish (FIN) AF: 0.820 AC: 8680 AN: 10586

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.785 AC: 53344 AN: 67996

Other (OTH) AF: 0.734 AC: 1554 AN: 2116

Alfa AF: 0.768 Hom.: 192235

Bravo AF: 0.710

Asia WGS AF: 0.742 AC: 2580 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	4.0
DANN	Benign	0.79
PhyloP100		-0.43
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: rs298988; hg19: chr4-119648399;