Genetic Variant SEC24D:c.2959-9_2959-6dupTTTT (chr4-118723660-G-GAAAA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_014822.4(SEC24D):c.2959-9_2959-6dupTTTT 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 1,287,542 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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.471

Publications

0 publications found

Variant links:

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

SEC24D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.2959-9_2959-6dupTTTT		splice_region intron	N/A	NP_055637.2	O94855-1
	SEC24D	NM_001318066.2		c.2962-9_2962-6dupTTTT		splice_region intron	N/A	NP_001304995.1	O94855-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SEC24D	ENST00000280551.11	TSL:1 MANE Select	c.2959-6_2959-5insTTTT	splice_region intron	N/A	ENSP00000280551.6	O94855-1
SEC24D	ENST00000511481.5	TSL:1	c.1852-6_1852-5insTTTT	splice_region intron	N/A	ENSP00000425491.1	E9PDM8
SEC24D	ENST00000924655.1		c.2959-6_2959-5insTTTT	splice_region intron	N/A	ENSP00000594714.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.77e-7

AC:

AN:

1287542

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

638828

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

27848

American (AMR)

AF:

0.00

AC:

AN:

33252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22268

East Asian (EAS)

AF:

0.00

AC:

AN:

33906

South Asian (SAS)

AF:

0.00

AC:

AN:

70468

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5220

European-Non Finnish (NFE)

AF:

0.00000100

AC:

AN:

995304

Other (OTH)

AF:

0.00

AC:

AN:

52642

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.125

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

4-118723660-GAAAA-GAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over