4-118723657-TA-T

Variant names:

• chr4-118723657-TA-T
• rs1317925665
• NM_014822.4:c.2959-3delT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014822.4(SEC24D):​c.2959-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000371 in 1,592,430 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: SEC24D NM_014822.4 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC24D	NM_014822.4	c.2959-3delT		splice_region_variant, intron_variant	Intron 22 of 22	ENST00000280551.11	NP_055637.2
SEC24D	NM_001318066.2	c.2962-3delT		splice_region_variant, intron_variant	Intron 22 of 22		NP_001304995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC24D	ENST00000280551.11	c.2959-3delT		splice_region_variant, intron_variant	Intron 22 of 22	1	NM_014822.4	ENSP00000280551.6
SEC24D	ENST00000511481.5	c.1852-3delT		splice_region_variant, intron_variant	Intron 15 of 15	1		ENSP00000425491.1
SEC24D	ENST00000502830.1	n.288-3delT		splice_region_variant, intron_variant	Intron 1 of 1	2
SEC24D	ENST00000505134.5	n.3090-3delT		splice_region_variant, intron_variant	Intron 17 of 17	2

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150710 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000442 AC: 1 AN: 226418 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00000955

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000395 AC: 57 AN: 1441720 Hom.: 0 Cov.: 30 AF XY: 0.0000335 AC XY: 24 AN XY: 716802

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 31786

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 39000

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25314

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39594

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 81588

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53032

Gnomad4 NFE exome AF: 0.0000461 AC: 51 AN: 1106366

Gnomad4 Remaining exome AF: 0.000101 AC: 6 AN: 59416

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150710 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73534

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000296 AC: 0.0000295718 AN: 0.0000295718

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.0000549

EpiControl AF: 0.0000596

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 22 of the SEC24D gene. It does not directly change the encoded amino acid sequence of the SEC24D protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with SEC24D-related conditions. ClinVar contains an entry for this variant (Variation ID: 1442023). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1317925665; hg19: chr4-119644812;