chr4-118723660-G-GAAA

Variant names:

• chr4-118723660-G-GAAA
• rs140990828
• NM_014822.4:c.2959-8_2959-6dupTTT

Variant summary

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

The NM_014822.4(SEC24D):​c.2959-8_2959-6dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000777 in 1,287,442 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: SEC24D NM_014822.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.471
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.2959-8_2959-6dupTTT		splice_region intron	N/A	NP_055637.2	O94855-1
	SEC24D	NM_001318066.2		c.2962-8_2962-6dupTTT		splice_region 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.2959-6_2959-5insTTT		splice_region intron	N/A	ENSP00000280551.6	O94855-1
	SEC24D	ENST00000511481.5	TSL:1	c.1852-6_1852-5insTTT		splice_region intron	N/A	ENSP00000425491.1	E9PDM8
	SEC24D	ENST00000924655.1		c.2959-6_2959-5insTTT		splice_region intron	N/A	ENSP00000594714.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 139688 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.77e-7 AC: 1 AN: 1287442 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 638776

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

African (AFR) AF: 0.00 AC: 0 AN: 27848

American (AMR) AF: 0.00 AC: 0 AN: 33250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22268

East Asian (EAS) AF: 0.00 AC: 0 AN: 33904

South Asian (SAS) AF: 0.00 AC: 0 AN: 70460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5220

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 995224

Other (OTH) AF: 0.00 AC: 0 AN: 52638

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.47

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140990828; hg19: chr4-119644815;