7-19725761-A-G

Position:

• chr7-19725761-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001363562.2(TMEM196):​c.212T>C​(p.Leu71Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM196 NM_001363562.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.71

Genes affected

TMEM196 (HGNC:22431): (transmembrane protein 196) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LOC107986774 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM196	NM_001363562.2	c.212T>C	p.Leu71Pro	missense_variant	3/5	ENST00000405844.6	NP_001350491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM196	ENST00000405844.6	c.212T>C	p.Leu71Pro	missense_variant	3/5	5	NM_001363562.2	ENSP00000385087.2
TMEM196	ENST00000405764.7	c.212T>C	p.Leu71Pro	missense_variant	3/4	1		ENSP00000384234.3
TMEM196	ENST00000422233.5	c.8T>C	p.Leu3Pro	missense_variant	3/5	5		ENSP00000414247.1
TMEM196	ENST00000493519.2	c.8T>C	p.Leu3Pro	missense_variant	3/4	5		ENSP00000438368.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441576 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 713720

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: 9.11e-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

Oct 26, 2024

The c.212T>C (p.L71P) alteration is located in exon 3 (coding exon 3) of the TMEM196 gene. This alteration results from a T to C substitution at nucleotide position 212, causing the leucine (L) at amino acid position 71 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
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Benign	-0.48	T
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.2	D;D;D;D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.98
MutPred		0.38		Loss of stability (P = 0.0279);Loss of stability (P = 0.0279);.;.;.;
MVP		0.36
MPC		0.041
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr7-19765384;