22-42409525-C-T

Variant names:

• chr22-42409525-C-T
• rs143813591
• NM_145912.8:c.474G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_145912.8(NFAM1):​c.474G>A​(p.Pro158Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00566 in 1,537,692 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0057 (31 hom.)
• Consequence: NFAM1 NM_145912.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -8.63
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 22-42409525-C-T is Benign according to our data. Variant chr22-42409525-C-T is described in ClinVar as Benign. ClinVar VariationId is 769482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00569 (7881/1385440) while in subpopulation MID AF = 0.0186 (102/5470). AF 95% confidence interval is 0.0157. There are 31 homozygotes in GnomAdExome4. There are 3929 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFAM1	NM_145912.8	MANE Select	c.474G>A	p.Pro158Pro	synonymous	Exon 3 of 6	NP_666017.1	Q8NET5
	NFAM1	NM_001371362.1		c.318G>A	p.Pro106Pro	synonymous	Exon 5 of 8	NP_001358291.1
	NFAM1	NM_001318323.3		c.451+1882G>A		intron	N/A	NP_001305252.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFAM1	ENST00000329021.10	TSL:1 MANE Select	c.474G>A	p.Pro158Pro	synonymous	Exon 3 of 6	ENSP00000333680.5	Q8NET5
	NFAM1	ENST00000968877.1		c.474G>A	p.Pro158Pro	synonymous	Exon 3 of 5	ENSP00000638936.1

Frequencies

GnomAD3 genomes AF: 0.00544 AC: 828 AN: 152134 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00600

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00714 AC: 1408 AN: 197296 AF XY: 0.00730

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00413

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.00711

Gnomad OTH exome AF: 0.00772

GnomAD4 exome AF: 0.00569 AC: 7881 AN: 1385440 Hom.: 31 Cov.: 28 AF XY: 0.00572 AC XY: 3929 AN XY: 687324

African (AFR) AF: 0.00114 AC: 34 AN: 29732

American (AMR) AF: 0.00305 AC: 105 AN: 34372

Ashkenazi Jewish (ASJ) AF: 0.00542 AC: 125 AN: 23064

East Asian (EAS) AF: 0.00 AC: 0 AN: 35178

South Asian (SAS) AF: 0.00330 AC: 252 AN: 76270

European-Finnish (FIN) AF: 0.0225 AC: 1172 AN: 51974

Middle Eastern (MID) AF: 0.0186 AC: 102 AN: 5470

European-Non Finnish (NFE) AF: 0.00538 AC: 5775 AN: 1072658

Other (OTH) AF: 0.00557 AC: 316 AN: 56722

GnomAD4 genome AF: 0.00543 AC: 827 AN: 152252 Hom.: 8 Cov.: 33 AF XY: 0.00627 AC XY: 467 AN XY: 74450

African (AFR) AF: 0.000891 AC: 37 AN: 41540

American (AMR) AF: 0.00412 AC: 63 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4820

European-Finnish (FIN) AF: 0.0258 AC: 274 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00600 AC: 408 AN: 68002

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00507 Hom.: 2

Bravo AF: 0.00421

Asia WGS AF: 0.00115 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.10
DANN	Benign	0.54
PhyloP100		-8.6
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs143813591; hg19: chr22-42805531; COSMIC: COSV61195021; COSMIC: COSV61195021;