17-75485929-C-A

Variant names:

• chr17-75485929-C-A
• rs753173127
• NM_014738.6:c.203C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014738.6(TMEM94):​c.203C>A​(p.Pro68Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,428 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P68L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM94 NM_014738.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.27
• 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 2 ACMG points.

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

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.203C>A	p.Pro68Gln	missense	Exon 4 of 32	NP_055553.3
	TMEM94	NM_001438842.1		c.203C>A	p.Pro68Gln	missense	Exon 4 of 32	NP_001425771.1
	TMEM94	NM_001438843.1		c.233C>A	p.Pro78Gln	missense	Exon 3 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.203C>A	p.Pro68Gln	missense	Exon 4 of 32	ENSP00000313885.7	Q12767-1
	TMEM94	ENST00000956011.1		c.203C>A	p.Pro68Gln	missense	Exon 4 of 32	ENSP00000626070.1
	TMEM94	ENST00000861539.1		c.203C>A	p.Pro68Gln	missense	Exon 4 of 32	ENSP00000531598.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461428 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727022

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Benign	0.93
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.65	D
PhyloP100		7.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.70
Sift	Benign	0.048	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.42		Gain of catalytic residue at P78 (P = 0.0022)
MVP		0.86
MPC		1.1
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.25
gMVP		0.55
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.47		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs753173127; hg19: chr17-73482010;