dbSNP rs749485474: FER1L5:p.Ala318Thr (chr2-96661725-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001293083.2(FER1L5):c.952G>A(p.Ala318Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A318P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

FER1L5
NM_001293083.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.819

Publications

0 publications found

Variant links:

Genes affected

FER1L5 (HGNC:19044): (fer-1 like family member 5) Predicted to enable calcium ion binding activity and calcium-dependent phospholipid binding activity. Predicted to be involved in several processes, including myeloid cell activation involved in immune response; negative regulation of phagocytosis; and plasma membrane organization. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. Predicted to be active in T-tubule and cytoplasmic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

FER1L5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052619696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FER1L5	NM_001293083.2 link	c.952G>A	p.Ala318Thr	missense_variant	Exon 12 of 53	ENST00000624922.6	NP_001280012.1	A0AVI2-1Q2NNQ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FER1L5	ENST00000624922.6 link	c.952G>A	p.Ala318Thr	missense_variant	Exon 12 of 53	5	NM_001293083.2	ENSP00000485238.1		A0AVI2-1
FER1L5	ENST00000623019.5 link	c.901G>A	p.Ala301Thr	missense_variant	Exon 11 of 52	6		ENSP00000493220.1		A0A286YFD1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000650

AC:

AN:

153956

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399392

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690204

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:

31598

American (AMR)

AF:

0.0000280

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078962

Other (OTH)

AF:

0.00

AC:

AN:

57998

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.044

(source)

DANN

Benign

0.78

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0088

LIST_S2

Benign

0.58

T;T;T

MetaRNN

Benign

0.053

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.82

PrimateAI

Benign

0.26

Sift4G

Benign

0.22

.;T;T

Vest4

0.073, 0.078

MutPred

0.52

.;.;Loss of catalytic residue at A301 (P = 0.0337);

MVP

0.014

ClinPred

0.044

GERP RS

-5.0

Varity_R

0.016

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Computational scores

Splicing

Publications

Other links and lift over