Genetic Variant SFN:p.Gly236Glu (chr1-26863919-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006142.5(SFN):c.707G>A(p.Gly236Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,516 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. G236R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SFN
NM_006142.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.87

Publications

0 publications found

Variant links:

Genes affected

SFN (HGNC:10773): (stratifin) This gene encodes a cell cycle checkpoint protein. The encoded protein binds to translation and initiation factors and functions as a regulator of mitotic translation. In response to DNA damage this protein plays a role in preventing DNA errors during mitosis. [provided by RefSeq, Aug 2017]

SFN links:

ENSG00000304862 (HGNC:):

ENSG00000304862 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2733205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFN	NM_006142.5 link	c.707G>A	p.Gly236Glu	missense_variant	Exon 1 of 1	ENST00000339276.6	NP_006133.1	P31947-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SFN	ENST00000339276.6 link	c.707G>A	p.Gly236Glu	missense_variant	Exon 1 of 1	6	NM_006142.5	ENSP00000340989.4	P31947-1
ENSG00000304862	ENST00000806706.1 link	n.93+1124C>T		intron_variant	Intron 1 of 1
ENSG00000304862	ENST00000806707.1 link	n.80+1124C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461516

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727070

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111858

Other (OTH)

AF:

0.00

AC:

AN:

60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 06, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.707G>A (p.G236E) alteration is located in exon 1 (coding exon 1) of the SFN gene. This alteration results from a G to A substitution at nucleotide position 707, causing the glycine (G) at amino acid position 236 to be replaced by a glutamic acid (E). 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

0.15

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0060

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.49

PhyloP100

4.9

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.5

REVEL

Benign

0.080

Sift

Benign

0.044

Sift4G

Benign

0.20

Polyphen

0.83

Vest4

0.30

MutPred

0.45

Gain of helix (P = 0.0199);

MVP

0.50

MPC

0.80

ClinPred

0.81

GERP RS

5.9

Varity_R

0.18

gMVP

0.38

Mutation Taster

=50/50

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over