6-37218926-C-A

Variant names:

• chr6-37218926-C-A
• rs757856760
• NM_001286401.2:c.105G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001286401.2(TMEM217):​c.105G>T​(p.Lys35Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K35Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TMEM217 NM_001286401.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.672

Genes affected

TMEM217 (HGNC:21238): (transmembrane protein 217) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM217B (HGNC:55922): (transmembrane protein 217B)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042829663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM217	NM_001286401.2	c.105G>T	p.Lys35Asn	missense_variant	Exon 2 of 3	ENST00000651039.2	NP_001273330.1
TMEM217B	NM_001395378.1	c.-27-5930G>T		intron_variant	Intron 1 of 1	ENST00000497775.2	NP_001382307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM217	ENST00000651039.2	c.105G>T	p.Lys35Asn	missense_variant	Exon 2 of 3		NM_001286401.2	ENSP00000499204.1
TMEM217B	ENST00000497775.2	c.-27-5930G>T		intron_variant	Intron 1 of 1	2	NM_001395378.1	ENSP00000499172.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251436 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.105G>T (p.K35N) alteration is located in exon 2 (coding exon 1) of the TMEM217 gene. This alteration results from a G to T substitution at nucleotide position 105, causing the lysine (K) at amino acid position 35 to be replaced by an asparagine (N). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.3
DANN	Benign	0.38
DEOGEN2	Benign	0.0092	.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.011
Sift	Benign	0.47	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0040	B;B
Vest4		0.26
MutPred		0.33		Loss of methylation at K35 (P = 0.009);Loss of methylation at K35 (P = 0.009);
MVP		0.030
MPC		0.32
ClinPred		0.020	T
GERP RS		-4.6
Varity_R		0.035
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs757856760; hg19: chr6-37186702;