NM_014822.4:c.*172A>G

Variant names:

• chr4-118723343-T-C
• rs79586191
• NM_014822.4:c.*172A>G

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.*172A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 578,128 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (5 hom.)
• Consequence: SEC24D NM_014822.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.37
• Publications: 1 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: 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-118723343-T-C is Benign according to our data. Variant chr4-118723343-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1181948.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 = 0.00743 (1131/152312) while in subpopulation AFR AF = 0.0253 (1052/41562). AF 95% confidence interval is 0.024. There are 7 homozygotes in GnomAd4. There are 541 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.*172A>G		3_prime_UTR	Exon 23 of 23	NP_055637.2	O94855-1
	SEC24D	NM_001318066.2		c.*172A>G		3_prime_UTR	Exon 23 of 23	NP_001304995.1	O94855-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC24D	ENST00000280551.11	TSL:1 MANE Select	c.*172A>G		3_prime_UTR	Exon 23 of 23	ENSP00000280551.6	O94855-1
	SEC24D	ENST00000511481.5	TSL:1	c.*172A>G		3_prime_UTR	Exon 16 of 16	ENSP00000425491.1	E9PDM8
	SEC24D	ENST00000924655.1		c.*172A>G		3_prime_UTR	Exon 23 of 23	ENSP00000594714.1

Frequencies

GnomAD3 genomes AF: 0.00741 AC: 1127 AN: 152194 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00102 AC: 434 AN: 425816 Hom.: 5 Cov.: 6 AF XY: 0.000932 AC XY: 207 AN XY: 222198

African (AFR) AF: 0.0264 AC: 313 AN: 11834

American (AMR) AF: 0.00238 AC: 35 AN: 14730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12508

East Asian (EAS) AF: 0.00 AC: 0 AN: 29370

South Asian (SAS) AF: 0.0000906 AC: 3 AN: 33116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28926

Middle Eastern (MID) AF: 0.00218 AC: 4 AN: 1836

European-Non Finnish (NFE) AF: 0.000126 AC: 34 AN: 268990

Other (OTH) AF: 0.00184 AC: 45 AN: 24506

GnomAD4 genome AF: 0.00743 AC: 1131 AN: 152312 Hom.: 7 Cov.: 32 AF XY: 0.00726 AC XY: 541 AN XY: 74472

African (AFR) AF: 0.0253 AC: 1052 AN: 41562

American (AMR) AF: 0.00372 AC: 57 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68018

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00308 Hom.: 1

Bravo AF: 0.00892

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.065
DANN	Benign	0.78
PhyloP100		-3.4
Mutation Taster		=100/0	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: rs79586191; hg19: chr4-119644498;