Genetic Variant SDF2L1:p.Arg148His (chr22-21643952-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_022044.3(SDF2L1):c.443G>A(p.Arg148His) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R148C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

SDF2L1
NM_022044.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.26

Variant links:

Genes affected

SDF2L1 (HGNC:10676): (stromal cell derived factor 2 like 1) Enables misfolded protein binding activity. Involved in chaperone cofactor-dependent protein refolding. Located in endoplasmic reticulum. Part of chaperone complex. [provided by Alliance of Genome Resources, Apr 2022]

SDF2L1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33714566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDF2L1	NM_022044.3 link	c.443G>A	p.Arg148His	missense_variant	Exon 3 of 3	ENST00000248958.5	NP_071327.2	Q9HCN8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDF2L1	ENST00000248958.5 link	c.443G>A	p.Arg148His	missense_variant	Exon 3 of 3	1	NM_022044.3	ENSP00000248958.4		Q9HCN8

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152162

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:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000108

AC:

AN:

250846

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135650

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000301

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.443G>A (p.R148H) alteration is located in exon 3 (coding exon 3) of the SDF2L1 gene. This alteration results from a G to A substitution at nucleotide position 443, causing the arginine (R) at amino acid position 148 to be replaced by a histidine (H). 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

0.079

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.34

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

0.59

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.96

REVEL

Uncertain

0.42

Sift

Benign

0.092

Sift4G

Benign

0.16

Polyphen

0.94

Vest4

0.30

MutPred

0.49

Loss of MoRF binding (P = 0.0831);

MVP

0.95

MPC

1.2

ClinPred

0.15

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.098

gMVP

0.55

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

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