19-54073959-C-T

Position:

• chr19-54073959-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001135686.3(TARM1):​c.619G>A​(p.Ala207Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000715 in 1,399,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: TARM1 NM_001135686.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.172

Genes affected

TARM1 (HGNC:37250): (T cell-interacting, activating receptor on myeloid cells 1) Enables immunoglobulin receptor binding activity. Involved in negative regulation of CD4-positive, alpha-beta T cell activation. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1452105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TARM1	NM_001135686.3	c.619G>A	p.Ala207Thr	missense_variant	4/5	ENST00000432826.2	NP_001129158.2
TARM1	NM_001330650.1	c.643G>A	p.Ala215Thr	missense_variant	4/5		NP_001317579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TARM1	ENST00000432826.2	c.619G>A	p.Ala207Thr	missense_variant	4/5	1	NM_001135686.3	ENSP00000439454	P2
TARM1	ENST00000616041.4	c.643G>A	p.Ala215Thr	missense_variant	4/5	2		ENSP00000484383	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000715 AC: 10 AN: 1399404 Hom.: 0 Cov.: 32 AF XY: 0.00000724 AC XY: 5 AN XY: 690212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000631

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2023

The c.619G>A (p.A207T) alteration is located in exon 4 (coding exon 4) of the TARM1 gene. This alteration results from a G to A substitution at nucleotide position 619, causing the alanine (A) at amino acid position 207 to be replaced by a threonine (T). 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	0.24
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.7
DANN	Benign	0.97
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.70	T;.
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	.;N
REVEL	Benign	0.041
Sift	Benign	0.47	.;T
Sift4G	Benign	0.55	T;T
Vest4		0.18
MutPred		0.48		.;Gain of phosphorylation at A207 (P = 0.0709);
MVP		0.040
ClinPred		0.38	T
GERP RS		1.9
gMVP		0.11

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: rs1477168514; hg19: chr19-54577211;