17-74795534-G-C

Position:

• chr17-74795534-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017728.4(TMEM104):​c.538G>C​(p.Gly180Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM104 NM_017728.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.37

Genes affected

TMEM104 (HGNC:25984): (transmembrane protein 104) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39523247).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM104	NM_017728.4	c.538G>C	p.Gly180Arg	missense_variant	8/10	ENST00000335464.10	NP_060198.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM104	ENST00000335464.10	c.538G>C	p.Gly180Arg	missense_variant	8/10	1	NM_017728.4	ENSP00000334849	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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 13, 2024

The c.538G>C (p.G180R) alteration is located in exon 8 (coding exon 7) of the TMEM104 gene. This alteration results from a G to C substitution at nucleotide position 538, causing the glycine (G) at amino acid position 180 to be replaced by an arginine (R). 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	0.090
BayesDel_addAF	Benign	-0.0088	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;T;.;.;T
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;.
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	L;.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	N;N;.;.;.
REVEL	Benign	0.22
Sift	Benign	0.22	T;.;.;.;.
Sift4G	Benign	0.36	T;T;T;T;T
Polyphen		0.99	D;D;.;D;D
Vest4		0.81
MVP		0.53
MPC		0.46
ClinPred		0.71	D
GERP RS		2.8
Varity_R		0.048
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200772320; hg19: chr17-72791673;