4-118723660-GAAAA-GAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_014822.4(SEC24D):c.2959-6dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.062 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, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.471

Publications

1 publications found

Variant links:

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

SEC24D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 1283265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0328 (4743/144470) while in subpopulation SAS AF = 0.0398 (179/4502). AF 95% confidence interval is 0.0374. There are 93 homozygotes in GnomAd4. There are 2237 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 93 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.2959-6dupT		splice_region intron	N/A	NP_055637.2	O94855-1
	SEC24D	NM_001318066.2		c.2962-6dupT		splice_region intron	N/A	NP_001304995.1	O94855-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SEC24D	ENST00000280551.11	TSL:1 MANE Select	c.2959-6_2959-5insT	splice_region intron	N/A	ENSP00000280551.6	O94855-1
SEC24D	ENST00000511481.5	TSL:1	c.1852-6_1852-5insT	splice_region intron	N/A	ENSP00000425491.1	E9PDM8
SEC24D	ENST00000924655.1		c.2959-6_2959-5insT	splice_region intron	N/A	ENSP00000594714.1

Frequencies

GnomAD3 genomes

AF:

0.0329

AC:

4744

AN:

144400

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0736

AC:

10275

AN:

139688

AF XY:

0.0747

show subpopulations

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 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.:

AF XY:

0.0666

AC XY:

36409

AN XY:

546546

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0495

AC:

1173

AN:

23720

American (AMR)

AF:

0.0577

AC:

1649

AN:

28568

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

2427

AN:

18976

East Asian (EAS)

AF:

0.0224

AC:

625

AN:

27926

South Asian (SAS)

AF:

0.0791

AC:

4607

AN:

58232

European-Finnish (FIN)

AF:

0.0451

AC:

1826

AN:

40478

Middle Eastern (MID)

AF:

0.110

AC:

517

AN:

4694

European-Non Finnish (NFE)

AF:

0.0660

AC:

56567

AN:

856500

Other (OTH)

AF:

0.0726

AC:

3257

AN:

44848

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.398

Heterozygous variant carriers

3594

7187

10781

14374

17968

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2072

4144

6216

8288

10360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0328

AC:

4743

AN:

144470

Hom.:

Cov.:

AF XY:

0.0318

AC XY:

2237

AN XY:

70250

show subpopulations

African (AFR)

AF:

0.0227

AC:

897

AN:

39448

American (AMR)

AF:

0.0309

AC:

447

AN:

14448

Ashkenazi Jewish (ASJ)

AF:

0.0878

AC:

297

AN:

3382

East Asian (EAS)

AF:

0.000597

AC:

AN:

5026

South Asian (SAS)

AF:

0.0398

AC:

179

AN:

4502

European-Finnish (FIN)

AF:

0.0197

AC:

177

AN:

8996

Middle Eastern (MID)

AF:

0.115

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0387

AC:

2532

AN:

65494

Other (OTH)

AF:

0.0475

AC:

AN:

2002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

228

456

683

911

1139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0571

Hom.:

Bravo

AF:

0.0309

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cole-Carpenter syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over