7-19725603-G-A

Variant summary

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

The NM_001363562.2(TMEM196):c.370C>T(p.Leu124Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM196 NM_001363562.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.46

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM196	NM_001363562.2	c.370C>T	p.Leu124Phe	missense_variant	3/5	ENST00000405844.6
LOC107986774	XR_001745112.2	n.1125+2461G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM196	ENST00000405844.6	c.370C>T	p.Leu124Phe	missense_variant	3/5	5	NM_001363562.2
TMEM196	ENST00000405764.7	c.370C>T	p.Leu124Phe	missense_variant	3/4	1		P1
TMEM196	ENST00000422233.5	c.166C>T	p.Leu56Phe	missense_variant	3/5	5
TMEM196	ENST00000493519.2	c.166C>T	p.Leu56Phe	missense_variant	3/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Feb 26, 2024

The c.370C>T (p.L124F) alteration is located in exon 3 (coding exon 3) of the TMEM196 gene. This alteration results from a C to T substitution at nucleotide position 370, causing the leucine (L) at amino acid position 124 to be replaced by a phenylalanine (F). 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	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.81
MutPred		0.18		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;.;.;
MVP		0.28
MPC		0.0088
ClinPred		0.99	D
GERP RS		5.7
gMVP		0.40

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: rs976155671; hg19: chr7-19765226;