3-68752991-C-T

Variant names:

• chr3-68752991-C-T
• rs201536721
• NM_182522.5:c.158G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_182522.5(TAFA4):​c.158G>A​(p.Cys53Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: TAFA4 NM_182522.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

Genes affected

TAFA4 (HGNC:21591): (TAFA chemokine like family member 4) This gene is a member of the TAFA family which is composed of five highly homologous genes that encode small secreted proteins. These proteins contain conserved cysteine residues at fixed positions, and are distantly related to MIP-1alpha, a member of the CC-chemokine family. The TAFA proteins are predominantly expressed in specific regions of the brain, and are postulated to function as brain-specific chemokines or neurokines, that act as regulators of immune and nervous cells. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFA4	NM_182522.5	c.158G>A	p.Cys53Tyr	missense_variant	Exon 4 of 6	ENST00000295569.12	NP_872328.1
TAFA4	NM_001005527.3	c.158G>A	p.Cys53Tyr	missense_variant	Exon 4 of 6		NP_001005527.1
TAFA4	XM_011533371.2	c.158G>A	p.Cys53Tyr	missense_variant	Exon 4 of 6		XP_011531673.1
TAFA4	XM_011533372.2	c.158G>A	p.Cys53Tyr	missense_variant	Exon 4 of 6		XP_011531674.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAFA4	ENST00000295569.12	c.158G>A	p.Cys53Tyr	missense_variant	Exon 4 of 6	1	NM_182522.5	ENSP00000295569.7
TAFA4	ENST00000495737.1	c.158G>A	p.Cys53Tyr	missense_variant	Exon 4 of 4	4		ENSP00000419439.1
TAFA4	ENST00000634242.1	c.158G>A	p.Cys53Tyr	missense_variant	Exon 7 of 7	5		ENSP00000489092.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000718 AC: 18 AN: 250774 Hom.: 0 AF XY: 0.0000738 AC XY: 10 AN XY: 135494

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32 AN XY: 727096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.158G>A (p.C53Y) alteration is located in exon 4 (coding exon 3) of the FAM19A4 gene. This alteration results from a G to A substitution at nucleotide position 158, causing the cysteine (C) at amino acid position 53 to be replaced by a tyrosine (Y). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;T
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.8	M;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-11	D;D;.
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.80		Loss of disorder (P = 0.0484);Loss of disorder (P = 0.0484);Loss of disorder (P = 0.0484);
MVP		0.23
MPC		1.0
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.90

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: rs201536721; hg19: chr3-68802142;