10-119898888-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_007190.4(SEC23IP):c.625C>T(p.Pro209Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00812 in 1,606,386 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (75 hom.)
• Consequence: SEC23IP NM_007190.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.33

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028744638).
• BP6: Variant 10-119898888-C-T is Benign according to our data. Variant chr10-119898888-C-T is described in ClinVar as [Benign]. Clinvar id is 771886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC23IP	NM_007190.4	c.625C>T	p.Pro209Ser	missense_variant	2/19	ENST00000369075.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC23IP	ENST00000369075.8	c.625C>T	p.Pro209Ser	missense_variant	2/19	1	NM_007190.4	P4
SEC23IP	ENST00000705471.1	c.625C>T	p.Pro209Ser	missense_variant	2/19			A1

Frequencies

GnomAD3 genomes AF: 0.00841 AC: 1280 AN: 152138 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00616

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0366

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00974

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00895 AC: 2197 AN: 245384 Hom.: 15 AF XY: 0.00905 AC XY: 1204 AN XY: 133098

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00443

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00370

Gnomad FIN exome AF: 0.0359

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.00809 AC: 11771 AN: 1454130 Hom.: 75 Cov.: 32 AF XY: 0.00803 AC XY: 5811 AN XY: 723690

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00432

Gnomad4 ASJ exome AF: 0.0130

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00373

Gnomad4 FIN exome AF: 0.0348

Gnomad4 NFE exome AF: 0.00787

Gnomad4 OTH exome AF: 0.00844

GnomAD4 genome AF: 0.00841 AC: 1280 AN: 152256 Hom.: 7 Cov.: 32 AF XY: 0.00912 AC XY: 679 AN XY: 74430

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00615

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.0366

Gnomad4 NFE AF: 0.00975

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00841 Hom.: 5

Bravo AF: 0.00545

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00901 AC: 1094

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.00954

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

SEC23IP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 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	0.067
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	12
Dann	Benign	0.70
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.69	N;.
REVEL	Benign	0.22
Sift	Benign	0.50	T;.
Sift4G	Benign	0.29	T;D
Polyphen		0.025	B;.
Vest4		0.20
MVP		0.87
MPC		0.13
ClinPred		0.011	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.15

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: rs148955366; hg19: chr10-121658400; COSMIC: COSV100957182; COSMIC: COSV100957182;