rs34157476

Positions:

• chr10-119902823-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_007190.4(SEC23IP):​c.721G>T​(p.Ala241Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,614,088 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.015 (22 hom., cov: 32)
  • Exomes 𝑓: 0.018 (293 hom.)
• Consequence: SEC23IP NM_007190.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.59

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033236146).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.015 (2288/152250) while in subpopulation AMR AF= 0.029 (444/15286). AF 95% confidence interval is 0.0268. There are 22 homozygotes in gnomad4. There are 1145 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEC23IP	NM_007190.4	c.721G>T	p.Ala241Ser	missense_variant	3/19	ENST00000369075.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEC23IP	ENST00000369075.8	c.721G>T	p.Ala241Ser	missense_variant	3/19	1	NM_007190.4	P4
SEC23IP	ENST00000705471.1	c.721G>T	p.Ala241Ser	missense_variant	3/19			A1
SEC23IP	ENST00000442952.1	c.19G>T	p.Ala7Ser	missense_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2292 AN: 152134 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.0201

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0157 AC: 3947 AN: 251370 Hom.: 45 AF XY: 0.0161 AC XY: 2187 AN XY: 135862

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0103

Gnomad FIN exome AF: 0.0220

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0222

GnomAD4 exome AF: 0.0179 AC: 26118 AN: 1461838 Hom.: 293 Cov.: 31 AF XY: 0.0177 AC XY: 12862 AN XY: 727222

Gnomad4 AFR exome AF: 0.00346

Gnomad4 AMR exome AF: 0.0159

Gnomad4 ASJ exome AF: 0.0246

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.0191

Gnomad4 OTH exome AF: 0.0201

GnomAD4 genome AF: 0.0150 AC: 2288 AN: 152250 Hom.: 22 Cov.: 32 AF XY: 0.0154 AC XY: 1145 AN XY: 74436

Gnomad4 AFR AF: 0.00337

Gnomad4 AMR AF: 0.0290

Gnomad4 ASJ AF: 0.0280

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00705

Gnomad4 FIN AF: 0.0201

Gnomad4 NFE AF: 0.0190

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0190 Hom.: 12

Bravo AF: 0.0149

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0210 AC: 81

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0200 AC: 172

ExAC AF: 0.0144 AC: 1754

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0246

EpiControl AF: 0.0218

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.0010
DANN	Benign	0.34
DEOGEN2	Benign	0.076	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.38	T;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.33	N;.
REVEL	Benign	0.020
Sift	Benign	0.31	T;.
Sift4G	Benign	0.82	T;T
Polyphen		0.0	B;.
Vest4		0.060
MPC		0.11
ClinPred		0.013	T
GERP RS		-9.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34157476; hg19: chr10-121662335; COSMIC: COSV99057882; COSMIC: COSV99057882;