7-66951014-C-T

Position:

• chr7-66951014-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017994.5(TMEM248):​c.659C>T​(p.Thr220Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM248 NM_017994.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.68

Genes affected

TMEM248 (HGNC:25476): (transmembrane protein 248) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM248	NM_017994.5	c.659C>T	p.Thr220Ile	missense_variant	5/7	ENST00000341567.8
TMEM248	XM_024446819.2	c.683C>T	p.Thr228Ile	missense_variant	5/7
TMEM248	XM_024446820.2	c.659C>T	p.Thr220Ile	missense_variant	5/7
TMEM248	XM_024446821.2	c.659C>T	p.Thr220Ile	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM248	ENST00000341567.8	c.659C>T	p.Thr220Ile	missense_variant	5/7	1	NM_017994.5	P1
TMEM248	ENST00000433271.6	c.597-2212C>T		intron_variant, NMD_transcript_variant		1
TMEM248	ENST00000484751.1	n.418C>T		non_coding_transcript_exon_variant	3/3	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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.659C>T (p.T220I) alteration is located in exon 5 (coding exon 4) of the TMEM248 gene. This alteration results from a C to T substitution at nucleotide position 659, causing the threonine (T) at amino acid position 220 to be replaced by an isoleucine (I). 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	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T
Eigen	Benign	0.021
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.51
Sift	Benign	0.36	T
Sift4G	Benign	0.074	T
Polyphen		0.89	P
Vest4		0.81
MutPred		0.44		Loss of sheet (P = 0.0126);
MVP		0.048
MPC		0.52
ClinPred		0.63	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1792251827; hg19: chr7-66416001;