4-118723660-G-GA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_014822.4(SEC24D):c.2959-6_2959-5insT 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 0.062 in 1,248,412 control chromosomes in the GnomAD database, including 585 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (93 hom., cov: 32)
  • Exomes 𝑓: 0.066 (492 hom.)
• Consequence: SEC24D NM_014822.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.471

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 -16 ACMG points.

• BP6: Variant 4-118723660-G-GA is Benign according to our data. Variant chr4-118723660-G-GA is described in ClinVar as [Benign]. Clinvar id is 1283265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC24D	NM_014822.4	c.2959-6_2959-5insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000280551.11
SEC24D	NM_001318066.2	c.2962-6_2962-5insT		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.2959-6_2959-5insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014822.4	P1
SEC24D	ENST00000511481.5	c.1852-6_1852-5insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
SEC24D	ENST00000502830.1	n.288-6_288-5insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2
SEC24D	ENST00000505134.5	n.3090-6_3090-5insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 4744 AN: 144400 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.0937

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.0878

Gnomad EAS AF: 0.000595

Gnomad SAS AF: 0.0399

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.110

Gnomad NFE AF: 0.0387

Gnomad OTH AF: 0.0479

GnomAD3 exomes AF: 0.0736 AC: 10275 AN: 139688 Hom.: 69 AF XY: 0.0747 AC XY: 5672 AN XY: 75930

Gnomad AFR exome AF: 0.0476

Gnomad AMR exome AF: 0.0793

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.0303

Gnomad SAS exome AF: 0.0977

Gnomad FIN exome AF: 0.0487

Gnomad NFE exome AF: 0.0732

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0658 AC: 72648 AN: 1103942 Hom.: 492 Cov.: 31 AF XY: 0.0666 AC XY: 36409 AN XY: 546546

Gnomad4 AFR exome AF: 0.0495

Gnomad4 AMR exome AF: 0.0577

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.0224

Gnomad4 SAS exome AF: 0.0791

Gnomad4 FIN exome AF: 0.0451

Gnomad4 NFE exome AF: 0.0660

Gnomad4 OTH exome AF: 0.0726

GnomAD4 genome AF: 0.0328 AC: 4743 AN: 144470 Hom.: 93 Cov.: 32 AF XY: 0.0318 AC XY: 2237 AN XY: 70250

Gnomad4 AFR AF: 0.0227

Gnomad4 AMR AF: 0.0309

Gnomad4 ASJ AF: 0.0878

Gnomad4 EAS AF: 0.000597

Gnomad4 SAS AF: 0.0398

Gnomad4 FIN AF: 0.0197

Gnomad4 NFE AF: 0.0387

Gnomad4 OTH AF: 0.0475

Bravo AF: 0.0309

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Cole-Carpenter syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs140990828; hg19: chr4-119644815;