4-118723660-GAAAA-GAAAAAA

Variant names:

• chr4-118723660-G-GAA
• rs140990828
• NM_014822.4:c.2959-7_2959-6dupTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_014822.4(SEC24D):​c.2959-7_2959-6dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,430,198 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SEC24D NM_014822.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.471
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 4-118723660-G-GAA is Benign according to our data. Variant chr4-118723660-G-GAA is described in ClinVar as Benign. ClinVar VariationId is 3673490.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2959-7_2959-6dupTT		splice_region intron	N/A	NP_055637.2	O94855-1
	SEC24D	NM_001318066.2		c.2962-7_2962-6dupTT		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_2959-5insTT		splice_region intron	N/A	ENSP00000280551.6	O94855-1
	SEC24D	ENST00000511481.5	TSL:1	c.1852-6_1852-5insTT		splice_region intron	N/A	ENSP00000425491.1	E9PDM8
	SEC24D	ENST00000924655.1		c.2959-6_2959-5insTT		splice_region intron	N/A	ENSP00000594714.1

Frequencies

GnomAD3 genomes AF: 0.00000692 AC: 1 AN: 144518 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: 0.0000153

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000265 AC: 37 AN: 139688 AF XY: 0.000237

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000314

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.000106

Gnomad FIN exome AF: 0.0000752

Gnomad NFE exome AF: 0.000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000158 AC: 203 AN: 1285680 Hom.: 0 Cov.: 31 AF XY: 0.000180 AC XY: 115 AN XY: 637908

⚠️ 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: 27830

American (AMR) AF: 0.000211 AC: 7 AN: 33222

Ashkenazi Jewish (ASJ) AF: 0.000675 AC: 15 AN: 22208

East Asian (EAS) AF: 0.00 AC: 0 AN: 33864

South Asian (SAS) AF: 0.000284 AC: 20 AN: 70300

European-Finnish (FIN) AF: 0.0000859 AC: 4 AN: 46578

Middle Eastern (MID) AF: 0.000576 AC: 3 AN: 5204

European-Non Finnish (NFE) AF: 0.000148 AC: 147 AN: 993928

Other (OTH) AF: 0.000133 AC: 7 AN: 52546

⚠️ 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 AF: 0.00000692 AC: 1 AN: 144518 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 70238

African (AFR) AF: 0.00 AC: 0 AN: 39382

American (AMR) AF: 0.00 AC: 0 AN: 14446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 5042

South Asian (SAS) AF: 0.00 AC: 0 AN: 4514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000153 AC: 1 AN: 65552

Other (OTH) AF: 0.00 AC: 0 AN: 1990

Alfa AF: 0.00116 Hom.: 12

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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;