chr22-42411592-C-T

Position:

• chr22-42411592-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145912.8(NFAM1):​c.266G>A​(p.Gly89Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NFAM1 NM_145912.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.616

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]

ACMG classification

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=0.38162154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFAM1	NM_145912.8	c.266G>A	p.Gly89Glu	missense_variant	2/6	ENST00000329021.10	NP_666017.1
NFAM1	NM_001371362.1	c.110G>A	p.Gly37Glu	missense_variant	4/8		NP_001358291.1
NFAM1	NM_001318323.3	c.266G>A	p.Gly89Glu	missense_variant	2/5		NP_001305252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFAM1	ENST00000329021.10	c.266G>A	p.Gly89Glu	missense_variant	2/6	1	NM_145912.8	ENSP00000333680	P1
NFAM1	ENST00000355469.4	n.271G>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.266G>A (p.G89E) alteration is located in exon 2 (coding exon 2) of the NFAM1 gene. This alteration results from a G to A substitution at nucleotide position 266, causing the glycine (G) at amino acid position 89 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	Uncertain	0.46
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.034
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.92	N
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.066
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.24		Gain of disorder (P = 0.0933);
MVP		0.58
MPC		0.40
ClinPred		0.84	D
GERP RS		4.1
Varity_R		0.23
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-42807598;