rs117971741

Variant names:

• chr4-118768317-G-C
• rs117971741
• NM_014822.4:c.1042-6C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014822.4(SEC24D):​c.1042-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,606,634 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (37 hom.)
• Consequence: SEC24D NM_014822.4 splice_region, intron
• Scores: Splicing: ADA: 0.0004669
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.920
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-118768317-G-C is Benign according to our data. Variant chr4-118768317-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00174 (265/151926) while in subpopulation EAS AF = 0.0434 (224/5166). AF 95% confidence interval is 0.0387. There are 6 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

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.1042-6C>G		splice_region intron	N/A	NP_055637.2	O94855-1
	SEC24D	NM_001318066.2		c.1045-6C>G		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.1042-6C>G		splice_region intron	N/A	ENSP00000280551.6	O94855-1
	SEC24D	ENST00000511481.5	TSL:1	c.-66-6C>G		splice_region intron	N/A	ENSP00000425491.1	E9PDM8
	SEC24D	ENST00000509818.5	TSL:1	n.*257-6C>G		splice_region intron	N/A	ENSP00000424085.1	D6RBM1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 267 AN: 151840 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0436

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.00409 AC: 1001 AN: 244480 AF XY: 0.00376

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.0000915

Gnomad ASJ exome AF: 0.00196

Gnomad EAS exome AF: 0.0520

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.00116 AC: 1688 AN: 1454708 Hom.: 37 Cov.: 31 AF XY: 0.00118 AC XY: 856 AN XY: 723602

African (AFR) AF: 0.0000910 AC: 3 AN: 32974

American (AMR) AF: 0.0000234 AC: 1 AN: 42704

Ashkenazi Jewish (ASJ) AF: 0.00190 AC: 49 AN: 25752

East Asian (EAS) AF: 0.0330 AC: 1308 AN: 39612

South Asian (SAS) AF: 0.00165 AC: 140 AN: 84644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1109906

Other (OTH) AF: 0.00278 AC: 167 AN: 60092

GnomAD4 genome AF: 0.00174 AC: 265 AN: 151926 Hom.: 6 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74216

African (AFR) AF: 0.000386 AC: 16 AN: 41428

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.0434 AC: 224 AN: 5166

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67978

Other (OTH) AF: 0.000477 AC: 1 AN: 2098

Alfa AF: 0.000406 Hom.: 1

Bravo AF: 0.00250

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cole-Carpenter syndrome 2 (1)
-	-	1	SEC24D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.99
DANN	Benign	0.59
PhyloP100		0.92
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.074
SpliceAI score (max)		0.070		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: rs117971741; hg19: chr4-119689472; COSMIC: COSV54880360; COSMIC: COSV54880360;