12-61867325-T-G

Variant names:

• chr12-61867325-T-G
• rs772431122
• NM_178539.5:c.101A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178539.5(TAFA2):​c.101A>C​(p.His34Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000282 in 1,420,916 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: 0.0000028 (0 hom.)
• Consequence: TAFA2 NM_178539.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78
• Publications: 0 publications found

Genes affected

TAFA2 (HGNC:21589): (TAFA chemokine like family member 2) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30547893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFA2	NM_178539.5	c.101A>C	p.His34Pro	missense_variant	Exon 2 of 5	ENST00000416284.8	NP_848634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAFA2	ENST00000416284.8	c.101A>C	p.His34Pro	missense_variant	Exon 2 of 5	1	NM_178539.5	ENSP00000393987.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1420916 Hom.: 0 Cov.: 28 AF XY: 0.00000424 AC XY: 3 AN XY: 707848

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000635 AC: 2 AN: 31508

American (AMR) AF: 0.00 AC: 0 AN: 39746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25756

East Asian (EAS) AF: 0.00 AC: 0 AN: 39394

South Asian (SAS) AF: 0.00 AC: 0 AN: 80610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52760

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5664

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086602

Other (OTH) AF: 0.0000170 AC: 1 AN: 58876

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.003830), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.101A>C (p.H34P) alteration is located in exon 2 (coding exon 1) of the FAM19A2 gene. This alteration results from a A to C substitution at nucleotide position 101, causing the histidine (H) at amino acid position 34 to be replaced by a proline (P). 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	Benign	0.073
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.0061	T;T;.;T;.;.
Eigen	Benign	-0.025
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.65	.;T;T;T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.31	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.81	L;L;.;.;.;.
PhyloP100		5.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.4	N;N;D;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.54	T;T;D;T;T;T
Sift4G	Benign	0.27	T;T;D;.;T;.
Polyphen		0.069	B;B;.;.;.;.
Vest4		0.83
MutPred		0.25		Gain of catalytic residue at K35 (P = 0);Gain of catalytic residue at K35 (P = 0);Gain of catalytic residue at K35 (P = 0);.;.;.;
MVP		0.67
MPC		1.1
ClinPred		0.39	T
GERP RS		5.8
Varity_R		0.31
gMVP		0.49
Mutation Taster		=44/56	disease causing

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: rs772431122; hg19: chr12-62261106;