rs6844109

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014822.4(SEC24D):c.578C>T(p.Pro193Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,144 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0054 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 13 hom. )

Consequence

SEC24D
NM_014822.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.52

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004474938).

BP6

Variant 4-118815546-G-A is Benign according to our data. Variant chr4-118815546-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-118815546-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00536 (816/152278) while in subpopulation AFR AF= 0.0154 (638/41556). AF 95% confidence interval is 0.0144. There are 4 homozygotes in gnomad4. There are 387 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC24D	NM_014822.4 link	c.578C>T	p.Pro193Leu	missense_variant	Exon 5 of 23	ENST00000280551.11	NP_055637.2	O94855-1A8K6V0
SEC24D	NM_001318066.2 link	c.578C>T	p.Pro193Leu	missense_variant	Exon 5 of 23		NP_001304995.1	O94855-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC24D	ENST00000280551.11 link	c.578C>T	p.Pro193Leu	missense_variant	Exon 5 of 23	1	NM_014822.4	ENSP00000280551.6		O94855-1

Frequencies

GnomAD3 genomes

AF:

0.00536

AC:

816

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00233

AC:

587

AN:

251482

Hom.:

AF XY:

0.00191

AC XY:

260

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0165

Gnomad AMR exome

AF:

0.00428

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00120

Gnomad OTH exome

AF:

0.00407

GnomAD4 exome

AF:

0.00137

AC:

2006

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

968

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0181

Gnomad4 AMR exome

AF:

0.00418

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000890

Gnomad4 OTH exome

AF:

0.00247

GnomAD4 genome

AF:

0.00536

AC:

816

AN:

152278

Hom.:

Cov.:

AF XY:

0.00520

AC XY:

387

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0154

Gnomad4 AMR

AF:

0.00392

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00131

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00208

Hom.:

Bravo

AF:

0.00657

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0150

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00227

AC:

275

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 13, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:1

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

9.5

DANN

Benign

0.91

DEOGEN2

Benign

0.024

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.22

Sift

Uncertain

0.029

Sift4G

Uncertain

0.0060

Polyphen

0.0

Vest4

0.20

MVP

0.53

MPC

0.17

ClinPred

0.0044

GERP RS

-0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.033

gMVP

0.088

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over