10-119919501-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_007190.4(SEC23IP):c.1930A>G(p.Lys644Glu) variant causes a missense change. The variant allele was found at a frequency of 0.683 in 1,612,424 control chromosomes in the GnomAD database, including 377,922 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.71 (38845 hom., cov: 31)
  • Exomes 𝑓: 0.68 (339077 hom.)
• Consequence: SEC23IP NM_007190.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.98

Genes affected

SEC23IP (HGNC:17018): (SEC23 interacting protein) This gene encodes a member of the phosphatidic acid preferring-phospholipase A1 family. The encoded protein is localized to endoplasmic reticulum exit sites and plays a critical role in ER-Golgi transport as part of the multimeric coat protein II complex. An orthologous gene in frogs is required for normal neural crest cell development, suggesting that this gene may play a role in Waardenburg syndrome neural crest defects. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.4852725E-7).
• BP6: Variant 10-119919501-A-G is Benign according to our data. Variant chr10-119919501-A-G is described in ClinVar as [Benign]. Clinvar id is 3059313.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC23IP	NM_007190.4	c.1930A>G	p.Lys644Glu	missense_variant	11/19	ENST00000369075.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC23IP	ENST00000369075.8	c.1930A>G	p.Lys644Glu	missense_variant	11/19	1	NM_007190.4	P4
SEC23IP	ENST00000705471.1	c.1930A>G	p.Lys644Glu	missense_variant	11/19			A1

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108193 AN: 151890 Hom.: 38798 Cov.: 31

Gnomad AFR AF: 0.784

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.723

Gnomad ASJ AF: 0.714

Gnomad EAS AF: 0.817

Gnomad SAS AF: 0.734

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.701

GnomAD3 exomes AF: 0.715 AC: 179039 AN: 250552 Hom.: 64378 AF XY: 0.713 AC XY: 96557 AN XY: 135458

Gnomad AFR exome AF: 0.784

Gnomad AMR exome AF: 0.761

Gnomad ASJ exome AF: 0.725

Gnomad EAS exome AF: 0.825

Gnomad SAS exome AF: 0.744

Gnomad FIN exome AF: 0.653

Gnomad NFE exome AF: 0.677

Gnomad OTH exome AF: 0.691

GnomAD4 exome AF: 0.680 AC: 992523 AN: 1460416 Hom.: 339077 Cov.: 36 AF XY: 0.682 AC XY: 495472 AN XY: 726536

Gnomad4 AFR exome AF: 0.785

Gnomad4 AMR exome AF: 0.757

Gnomad4 ASJ exome AF: 0.718

Gnomad4 EAS exome AF: 0.830

Gnomad4 SAS exome AF: 0.743

Gnomad4 FIN exome AF: 0.652

Gnomad4 NFE exome AF: 0.663

Gnomad4 OTH exome AF: 0.689

GnomAD4 genome AF: 0.712 AC: 108293 AN: 152008 Hom.: 38845 Cov.: 31 AF XY: 0.714 AC XY: 53091 AN XY: 74306

Gnomad4 AFR AF: 0.784

Gnomad4 AMR AF: 0.723

Gnomad4 ASJ AF: 0.714

Gnomad4 EAS AF: 0.817

Gnomad4 SAS AF: 0.735

Gnomad4 FIN AF: 0.656

Gnomad4 NFE AF: 0.668

Gnomad4 OTH AF: 0.701

Alfa AF: 0.683 Hom.: 74625

Bravo AF: 0.718

TwinsUK AF: 0.668 AC: 2476

ALSPAC AF: 0.659 AC: 2540

ESP6500AA AF: 0.779 AC: 3432

ESP6500EA AF: 0.672 AC: 5783

ExAC AF: 0.716 AC: 86941

Asia WGS AF: 0.745 AC: 2594 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SEC23IP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	17
Dann	Benign	0.76
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	6.5e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.6	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.084
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.042
MPC		0.17
ClinPred		0.0065	T
GERP RS		5.2
Varity_R		0.15
gMVP		0.18

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

Other links and lift over

dbSNP: rs2475298; hg19: chr10-121679013; COSMIC: COSV64832582; COSMIC: COSV64832582;