Genetic Variant NM_145912.8:c.575G>T (chr22-42397946-C-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_145912.8(NFAM1):c.575G>T(p.Arg192Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. R192W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NFAM1
NM_145912.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.97

Publications

0 publications found

Variant links:

Genes affected

NFAM1 (HGNC:29872): (NFAT activating protein with ITAM motif 1) The protein encoded by this gene is a type I membrane receptor that activates cytokine gene promoters such as the IL-13 and TNF-alpha promoters. The encoded protein contains an immunoreceptor tyrosine-based activation motif (ITAM) and is thought to regulate the signaling and development of B-cells. [provided by RefSeq, Jul 2008]

NFAM1 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=0.0436877).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145912.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NFAM1	NM_145912.8	MANE Select	c.575G>T	p.Arg192Leu	missense	Exon 4 of 6	NP_666017.1	Q8NET5
NFAM1	NM_001371362.1		c.419G>T	p.Arg140Leu	missense	Exon 6 of 8	NP_001358291.1
NFAM1	NM_001318323.3		c.462G>T	p.Ala154Ala	synonymous	Exon 3 of 5	NP_001305252.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFAM1	ENST00000329021.10	TSL:1 MANE Select	c.575G>T	p.Arg192Leu	missense	Exon 4 of 6	ENSP00000333680.5	Q8NET5
	NFAM1	ENST00000968877.1		c.575G>T	p.Arg192Leu	missense	Exon 4 of 5	ENSP00000638936.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

238620

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

6.93e-7

AC:

AN:

1443290

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32772

American (AMR)

AF:

0.00

AC:

AN:

42484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25290

East Asian (EAS)

AF:

0.00

AC:

AN:

39378

South Asian (SAS)

AF:

0.00

AC:

AN:

84952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52948

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100110

Other (OTH)

AF:

0.0000168

AC:

AN:

59670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.015

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.014

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.29

M_CAP

Benign

0.0029

MetaRNN

Benign

0.044

MetaSVM

Benign

-1.0

PhyloP100

-3.0

PrimateAI

Benign

0.18

PROVEAN

Benign

-0.22

REVEL

Benign

0.0

Sift

Benign

0.38

Sift4G

Benign

0.55

Polyphen

0.0010

Vest4

0.10

MutPred

0.32

Loss of solvent accessibility (P = 0.0098)

MVP

0.088

MPC

0.069

ClinPred

0.15

GERP RS

-7.5

Varity_R

0.039

gMVP

0.21

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over