rs117971741

chr4-118768317-G-C

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004669
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.920

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

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC24D	NM_014822.4	c.1042-6C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000280551.11
SEC24D	NM_001318066.2	c.1045-6C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC24D	ENST00000280551.11	c.1042-6C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014822.4	P1

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

GnomAD3 exomes AF: 0.00409 AC: 1001 AN: 244480 Hom.: 33 AF XY: 0.00376 AC XY: 497 AN XY: 132022

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 SAS exome AF: 0.00114

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

Gnomad4 AFR exome AF: 0.0000910

Gnomad4 AMR exome AF: 0.0000234

Gnomad4 ASJ exome AF: 0.00190

Gnomad4 EAS exome AF: 0.0330

Gnomad4 SAS exome AF: 0.00165

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00278

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

Gnomad4 AFR AF: 0.000386

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0434

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.000477

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

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

SEC24D-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cole-Carpenter syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.99
Dann	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs117971741; hg19: chr4-119689472; COSMIC: COSV54880360; COSMIC: COSV54880360;