4-118723660-GA-G

Position:

• chr4-118723660-GA-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP6_Moderate BS1

The NM_014822.4(SEC24D):​c.2959-6del 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 0.000116 in 1,430,820 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SEC24D NM_014822.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 4-118723660-GA-G is Benign according to our data. Variant chr4-118723660-GA-G is described in ClinVar as [Benign]. Clinvar id is 2052472.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-118723660-GA-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000899 (13/144588) while in subpopulation EAS AF= 0.00179 (9/5026). AF 95% confidence interval is 0.000934. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0000900 AC: 13 AN: 144518 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00179

Gnomad SAS AF: 0.000222

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000153

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00145 AC: 203 AN: 139688 Hom.: 0 AF XY: 0.00145 AC XY: 110 AN XY: 75930

Gnomad AFR exome AF: 0.000977

Gnomad AMR exome AF: 0.000628

Gnomad ASJ exome AF: 0.00262

Gnomad EAS exome AF: 0.00264

Gnomad SAS exome AF: 0.000508

Gnomad FIN exome AF: 0.000451

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000119 AC: 153 AN: 1286232 Hom.: 0 Cov.: 31 AF XY: 0.000122 AC XY: 78 AN XY: 638146

Gnomad4 AFR exome AF: 0.0000719

Gnomad4 AMR exome AF: 0.000362

Gnomad4 ASJ exome AF: 0.0000449

Gnomad4 EAS exome AF: 0.000945

Gnomad4 SAS exome AF: 0.000298

Gnomad4 FIN exome AF: 0.000129

Gnomad4 NFE exome AF: 0.0000754

Gnomad4 OTH exome AF: 0.0000761

GnomAD4 genome AF: 0.0000899 AC: 13 AN: 144588 Hom.: 0 Cov.: 32 AF XY: 0.000114 AC XY: 8 AN XY: 70316

Gnomad4 AFR AF: 0.0000507

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00179

Gnomad4 SAS AF: 0.000222

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000153

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000106

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;