chr22-42385192-C-G

Position:

• chr22-42385192-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_145912.8(NFAM1):​c.782G>C​(p.Gly261Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,612,914 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: NFAM1 NM_145912.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.821

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002138406).
• BP6: Variant 22-42385192-C-G is Benign according to our data. Variant chr22-42385192-C-G is described in ClinVar as [Benign]. Clinvar id is 711090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1633/152260) while in subpopulation AFR AF= 0.0371 (1541/41540). AF 95% confidence interval is 0.0356. There are 27 homozygotes in gnomad4. There are 757 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFAM1	NM_145912.8	c.782G>C	p.Gly261Ala	missense_variant	6/6	ENST00000329021.10	NP_666017.1
NFAM1	NM_001371362.1	c.626G>C	p.Gly209Ala	missense_variant	8/8		NP_001358291.1
NFAM1	NM_001318323.3	c.*72G>C		3_prime_UTR_variant	5/5		NP_001305252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFAM1	ENST00000329021.10	c.782G>C	p.Gly261Ala	missense_variant	6/6	1	NM_145912.8	ENSP00000333680.5

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1631 AN: 152142 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00278 AC: 695 AN: 250180 Hom.: 15 AF XY: 0.00204 AC XY: 276 AN XY: 135352

Gnomad AFR exome AF: 0.0357

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000302

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00121 AC: 1762 AN: 1460654 Hom.: 30 Cov.: 29 AF XY: 0.00106 AC XY: 773 AN XY: 726822

Gnomad4 AFR exome AF: 0.0359

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.0107 AC: 1633 AN: 152260 Hom.: 27 Cov.: 32 AF XY: 0.0102 AC XY: 757 AN XY: 74446

Gnomad4 AFR AF: 0.0371

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00181 Hom.: 5

Bravo AF: 0.0120

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0356 AC: 157

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00349 AC: 424

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.87
DANN	Benign	0.71
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.0060
Sift	Benign	0.089	T
Sift4G	Benign	0.21	T
Polyphen		0.21	B
Vest4		0.11
MVP		0.19
MPC		0.074
ClinPred		0.0010	T
GERP RS		0.13
Varity_R		0.030
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs151280792; hg19: chr22-42781198;