17-75485994-G-C

Variant names:

• chr17-75485994-G-C
• rs759987717
• NM_014738.6:c.268G>C

Variant summary

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

The NM_014738.6(TMEM94):​c.268G>C​(p.Gly90Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM94 NM_014738.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.10
• Publications: 1 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.268G>C	p.Gly90Arg	missense	Exon 4 of 32	NP_055553.3
	TMEM94	NM_001438842.1		c.268G>C	p.Gly90Arg	missense	Exon 4 of 32	NP_001425771.1
	TMEM94	NM_001438843.1		c.298G>C	p.Gly100Arg	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.268G>C	p.Gly90Arg	missense	Exon 4 of 32	ENSP00000313885.7	Q12767-1
	TMEM94	ENST00000956011.1		c.268G>C	p.Gly90Arg	missense	Exon 4 of 32	ENSP00000626070.1
	TMEM94	ENST00000861539.1		c.268G>C	p.Gly90Arg	missense	Exon 4 of 32	ENSP00000531598.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000419 AC: 1 AN: 238792 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000940

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Benign	0.86
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.36	D
PhyloP100		9.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.51
Sift	Benign	0.036	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.20		Gain of methylation at G100 (P = 0.0383)
MVP		0.85
MPC		1.3
ClinPred		0.79	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.74
Mutation Taster		=46/54	disease causing

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: rs759987717; hg19: chr17-73482075;