chr17-75486339-C-G

Variant names:

• chr17-75486339-C-G
• rs762218438
• NM_014738.6:c.322C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014738.6(TMEM94):​c.322C>G​(p.Leu108Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L108F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM94 NM_014738.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29
• Publications: 0 publications found

Genes affected

TMEM94 (HGNC:28983): (transmembrane protein 94) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM94 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with cardiac defects and dysmorphic facies

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet, ClinGen, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37728494).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014738.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM94	NM_014738.6	MANE Select	c.322C>G	p.Leu108Val	missense	Exon 5 of 32	NP_055553.3
	TMEM94	NM_001438842.1		c.322C>G	p.Leu108Val	missense	Exon 5 of 32	NP_001425771.1
	TMEM94	NM_001438843.1		c.352C>G	p.Leu118Val	missense	Exon 4 of 31	NP_001425772.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM94	ENST00000314256.12	TSL:1 MANE Select	c.322C>G	p.Leu108Val	missense	Exon 5 of 32	ENSP00000313885.7	Q12767-1
	TMEM94	ENST00000956011.1		c.322C>G	p.Leu108Val	missense	Exon 5 of 32	ENSP00000626070.1
	TMEM94	ENST00000861539.1		c.322C>G	p.Leu108Val	missense	Exon 5 of 32	ENSP00000531598.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Benign	0.038	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.33	D
PhyloP100		2.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.27	N
REVEL	Uncertain	0.31
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.45
MutPred		0.32		Gain of MoRF binding (P = 0.093)
MVP		0.86
MPC		0.67
ClinPred		0.72	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.63
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs762218438; hg19: chr17-73482420;