rs6844109

Variant names:

• chr4-118815546-G-A
• rs6844109
• NM_014822.4:c.578C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P193T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0054 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (13 hom.)
• Consequence: SEC24D NM_014822.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.52
• Publications: 7 publications found

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: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 377240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC24D	NM_014822.4	MANE Select	c.578C>T	p.Pro193Leu	missense	Exon 5 of 23	NP_055637.2
	SEC24D	NM_001318066.2		c.578C>T	p.Pro193Leu	missense	Exon 5 of 23	NP_001304995.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC24D	ENST00000280551.11	TSL:1 MANE Select	c.578C>T	p.Pro193Leu	missense	Exon 5 of 23	ENSP00000280551.6
	SEC24D	ENST00000509818.5	TSL:1	n.429C>T		non_coding_transcript_exon	Exon 4 of 12	ENSP00000424085.1
	SEC24D	ENST00000514561.5	TSL:1	n.*552C>T		non_coding_transcript_exon	Exon 6 of 23	ENSP00000422717.1

Frequencies

GnomAD3 genomes AF: 0.00536 AC: 816 AN: 152160 Hom.: 4 Cov.: 32

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

GnomAD2 exomes AF: 0.00233 AC: 587 AN: 251482 AF XY: 0.00191

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 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.: 13 Cov.: 54 AF XY: 0.00133 AC XY: 968 AN XY: 727232

African (AFR) AF: 0.0181 AC: 605 AN: 33480

American (AMR) AF: 0.00418 AC: 187 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86256

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.000890 AC: 990 AN: 1111986

Other (OTH) AF: 0.00247 AC: 149 AN: 60396

GnomAD4 genome AF: 0.00536 AC: 816 AN: 152278 Hom.: 4 Cov.: 32 AF XY: 0.00520 AC XY: 387 AN XY: 74472

African (AFR) AF: 0.0154 AC: 638 AN: 41556

American (AMR) AF: 0.00392 AC: 60 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68012

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00297 Hom.: 4

Bravo AF: 0.00657

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00227 AC: 275

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.5
DANN	Benign	0.91
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.5
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.22
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.0	B
Vest4		0.20
MVP		0.53
MPC		0.17
ClinPred		0.0044	T
GERP RS		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.033
gMVP		0.088
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs6844109; hg19: chr4-119736701;