chr12-61867361-G-A

Variant names:

• chr12-61867361-G-A
• rs751468007
• NM_178539.5:c.65C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_178539.5(TAFA2):​c.65C>T​(p.Thr22Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,136 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T22N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TAFA2 NM_178539.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.21
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAFA2	NM_178539.5	c.65C>T	p.Thr22Ile	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.65C>T	p.Thr22Ile	missense_variant	Exon 2 of 5	1	NM_178539.5	ENSP00000393987.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458136 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 725540

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

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39570

South Asian (SAS) AF: 0.00 AC: 0 AN: 85964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1109380

Other (OTH) AF: 0.0000166 AC: 1 AN: 60242

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.043001), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	T;T;.;T;.;.
Eigen	Benign	0.084
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D;D;D;D;D
M_CAP	Benign	0.0064	T
MetaRNN	Uncertain	0.58	D;D;D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.34	N;N;.;.;.;.
PhyloP100		7.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.1	N;N;D;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.16	T;T;D;T;T;T
Sift4G	Benign	0.50	T;T;D;.;T;.
Polyphen		0.063	B;B;.;.;.;.
Vest4		0.88
MutPred		0.40		Gain of catalytic residue at L23 (P = 0.002);Gain of catalytic residue at L23 (P = 0.002);Gain of catalytic residue at L23 (P = 0.002);.;.;.;
MVP		0.72
MPC		0.66
ClinPred		0.84	D
GERP RS		5.9
Varity_R		0.17
gMVP		0.36
Mutation Taster		=50/50

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: rs751468007; hg19: chr12-62261142;