chr12-71697433-C-T

Position:

• chr12-71697433-C-T

Variant summary

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

The ENST00000266673.10(TMEM19):​c.536C>T​(p.Ala179Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,914 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A179S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM19 ENST00000266673.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

Genes affected

TMEM19 (HGNC:25605): (transmembrane protein 19) Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000258064 (HGNC:):

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, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM19	NM_018279.4	c.536C>T	p.Ala179Val	missense_variant	4/6	ENST00000266673.10	NP_060749.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM19	ENST00000266673.10	c.536C>T	p.Ala179Val	missense_variant	4/6	1	NM_018279.4	ENSP00000266673.5
ENSG00000258064	ENST00000548802.1	n.*346C>T		non_coding_transcript_exon_variant	4/5	3		ENSP00000454911.2
ENSG00000258064	ENST00000548802.1	n.*346C>T		3_prime_UTR_variant	4/5	3		ENSP00000454911.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458914 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725762

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 08, 2022

The c.536C>T (p.A179V) alteration is located in exon 4 (coding exon 4) of the TMEM19 gene. This alteration results from a C to T substitution at nucleotide position 536, causing the alanine (A) at amino acid position 179 to be replaced by a valine (V). 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	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.2	M;M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N;D;N;N
REVEL	Uncertain	0.50
Sift	Benign	0.070	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.72
MutPred		0.76		Gain of catalytic residue at A179 (P = 0.1951);Gain of catalytic residue at A179 (P = 0.1951);.;.;
MVP		0.20
MPC		0.33
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-72091213;