Variant chr11-18000557-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012139.4(SERGEF):c.448C>T(p.Leu150Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SERGEF
NM_012139.4 missense, splice_region

Scores

Splicing: ADA: 0.001650

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.568

Variant links:

Genes affected

SERGEF (HGNC:17499): (secretion regulating guanine nucleotide exchange factor) Predicted to enable guanyl-nucleotide exchange factor activity. Involved in negative regulation of protein secretion. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SERGEF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08965883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SERGEF	NM_012139.4 linkuse as main transcript	c.448C>T	p.Leu150Phe	missense_variant, splice_region_variant	5/11	ENST00000265965.10	NP_036271.1
SERGEF	NR_104040.2 linkuse as main transcript	n.485C>T		splice_region_variant, non_coding_transcript_exon_variant	5/12
SERGEF	NR_104041.2 linkuse as main transcript	n.485C>T		splice_region_variant, non_coding_transcript_exon_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERGEF	ENST00000265965.10 linkuse as main transcript	c.448C>T	p.Leu150Phe	missense_variant, splice_region_variant	5/11	1	NM_012139.4	ENSP00000265965	P1	Q9UGK8-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000445

AC:

AN:

224610

Hom.:

AF XY:

0.00

AC XY:

AN XY:

121870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000616

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1428940

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710658

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The c.448C>T (p.L150F) alteration is located in exon 5 (coding exon 5) of the SERGEF gene. This alteration results from a C to T substitution at nucleotide position 448, causing the leucine (L) at amino acid position 150 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;.;T;.;T;.;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.54

T;T;T;T;T;T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.090

T;T;T;T;T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.3

L;L;.;.;.;.;.

MutationTaster

Benign

0.97

N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.5

N;N;N;N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.74

T;T;T;T;T;T;T

Sift4G

Benign

0.49

T;T;T;T;.;.;.

Polyphen

0.55

P;B;.;P;P;.;.

Vest4

0.064

MutPred

0.37

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;.;.;.;

MVP

0.77

MPC

0.21

ClinPred

0.19

GERP RS

1.8

Varity_R

0.028

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0016

dbscSNV1_RF

Benign

0.082

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over