Genetic Variant SEC23IP:p.Ala45Thr (chr10-119892915-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 13/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.89

Publications

8 publications found

Variant links:

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]

SEC23IP links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007190.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEC23IP	NM_007190.4	MANE Select	c.133G>A	p.Ala45Thr	missense	Exon 1 of 19	NP_009121.1	Q9Y6Y8-1
SEC23IP	NM_001411070.1		c.133G>A	p.Ala45Thr	missense	Exon 1 of 19	NP_001397999.1	A0A994J542
SEC23IP	NR_037771.2		n.186G>A		non_coding_transcript_exon	Exon 1 of 18

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEC23IP	ENST00000369075.8	TSL:1 MANE Select	c.133G>A	p.Ala45Thr	missense	Exon 1 of 19	ENSP00000358071.3	Q9Y6Y8-1
SEC23IP	ENST00000875162.1		c.133G>A	p.Ala45Thr	missense	Exon 1 of 20	ENSP00000545221.1
SEC23IP	ENST00000970232.1		c.133G>A	p.Ala45Thr	missense	Exon 1 of 19	ENSP00000640291.1

Frequencies

GnomAD3 genomes

AF:

0.00974

AC:

1482

AN:

152168

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00253

AC:

633

AN:

249730

AF XY:

0.00187

show subpopulations

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 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.:

Cov.:

AF XY:

0.000819

AC XY:

595

AN XY:

726728

show subpopulations

African (AFR)

AF:

0.0343

AC:

1147

AN:

33420

American (AMR)

AF:

0.00155

AC:

AN:

44580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000351

AC:

AN:

1111506

Other (OTH)

AF:

0.00197

AC:

119

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

129

194

258

323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00974

AC:

1484

AN:

152286

Hom.:

Cov.:

AF XY:

0.00947

AC XY:

705

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0343

AC:

1424

AN:

41550

American (AMR)

AF:

0.00248

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68020

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

143

214

286

357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00332

Hom.:

Bravo

AF:

0.0111

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0315

AC:

139

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00309

AC:

375

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

SEC23IP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0033

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

1.9

PhyloP100

3.9

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.010

REVEL

Benign

0.26

Sift

Uncertain

0.022

Sift4G

Benign

0.16

Polyphen

0.016

Vest4

0.38

MVP

0.89

MPC

0.14

ClinPred

0.028

GERP RS

5.1

PromoterAI

-0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.046

gMVP

0.37

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over