rs2101595858

Variant names:

• chr1-156291441-G-C
• rs2101595858
• NM_032323.3:c.1028G>C

Variant summary

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

The NM_032323.3(TMEM79):​c.1028G>C​(p.Gly343Ala) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM79 NM_032323.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.12

Genes affected

TMEM79 (HGNC:28196): (transmembrane protein 79) Enables identical protein binding activity. Predicted to be involved in several processes, including epithelial cell maturation; establishment of skin barrier; and positive regulation of epidermis development. Predicted to act upstream of or within cornification; cuticle development; and hair follicle morphogenesis. Predicted to be located in cytoplasm. Predicted to be active in lysosomal membrane and trans-Golgi network membrane. [provided by Alliance of Genome Resources, Apr 2022]

SMG5 (HGNC:24644): (SMG5 nonsense mediated mRNA decay factor) SMG5 is involved in nonsense-mediated mRNA decay (Ohnishi et al., 2003 [PubMed 14636577]).[supplied by OMIM, Mar 2008]

GLMP (HGNC:29436): (glycosylated lysosomal membrane protein) Involved in positive regulation of transcription by RNA polymerase II. Located in cytosol; lysosome; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.39468566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM79	NM_032323.3	c.1028G>C	p.Gly343Ala	missense_variant	Exon 4 of 4	ENST00000405535.3	NP_115699.1
SMG5	NM_001323617.2	c.-318C>G		5_prime_UTR_variant	Exon 1 of 23		NP_001310546.1
TMEM79	NR_026678.2	n.1205G>C		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM79	ENST00000405535.3	c.1028G>C	p.Gly343Ala	missense_variant	Exon 4 of 4	1	NM_032323.3	ENSP00000384748.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1028G>C (p.G343A) alteration is located in exon 4 (coding exon 3) of the TMEM79 gene. This alteration results from a G to C substitution at nucleotide position 1028, causing the glycine (G) at amino acid position 343 to be replaced by an alanine (A). 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	0.28
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.052	T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	.;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.1	L;L
PhyloP100		7.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.22
Sift	Benign	0.16	T;T
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;D
Vest4		0.39
MutPred		0.57		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.75
MPC		0.54
ClinPred		0.89	D
GERP RS		5.7
Varity_R		0.27
gMVP		0.68
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

Publications

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Other links and lift over

dbSNP: rs2101595858; hg19: chr1-156261232;