10-119892915-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007190.4(SEC23IP):c.133G>A(p.Ala45Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00178 in 1,613,074 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (26 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (32 hom.)
• Consequence: SEC23IP NM_007190.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.89

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032828152).
• BP6: Variant 10-119892915-G-A is Benign according to our data. Variant chr10-119892915-G-A is described in ClinVar as [Benign]. Clinvar id is 780914.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 = 0.00974 (1484/152286) while in subpopulation AFR AF= 0.0343 (1424/41550). AF 95% confidence interval is 0.0328. There are 26 homozygotes in gnomad4. There are 705 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC23IP	NM_007190.4	c.133G>A	p.Ala45Thr	missense_variant	1/19	ENST00000369075.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC23IP	ENST00000369075.8	c.133G>A	p.Ala45Thr	missense_variant	1/19	1	NM_007190.4	P4
SEC23IP	ENST00000705471.1	c.133G>A	p.Ala45Thr	missense_variant	1/19			A1
SEC23IP	ENST00000470478.1	n.171G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00974 AC: 1482 AN: 152168 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00248

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00253 AC: 633 AN: 249730 Hom.: 11 AF XY: 0.00187 AC XY: 253 AN XY: 135070

Gnomad AFR exome AF: 0.0349

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000973

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000946 AC: 1382 AN: 1460788 Hom.: 32 Cov.: 31 AF XY: 0.000819 AC XY: 595 AN XY: 726728

Gnomad4 AFR exome AF: 0.0343

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00974 AC: 1484 AN: 152286 Hom.: 26 Cov.: 32 AF XY: 0.00947 AC XY: 705 AN XY: 74472

Gnomad4 AFR AF: 0.0343

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.000472 Hom.: 1

Bravo AF: 0.0111

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0315 AC: 139

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00309 AC: 375

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

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

Nov 15, 2018

- -

SEC23IP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 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	0.080
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.010	N;.
REVEL	Benign	0.26
Sift	Uncertain	0.022	D;.
Sift4G	Benign	0.16	T;T
Polyphen		0.016	B;.
Vest4		0.38
MVP		0.89
MPC		0.14
ClinPred		0.028	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.37

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: rs73357833; hg19: chr10-121652427;