7-66953254-T-C

Variant names:

• chr7-66953254-T-C
• NM_017994.5:c.809T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017994.5(TMEM248):​c.809T>C​(p.Leu270Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 7.55

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM248	NM_017994.5	c.809T>C	p.Leu270Pro	missense_variant	Exon 6 of 7	ENST00000341567.8	NP_060464.1
TMEM248	XM_024446819.2	c.833T>C	p.Leu278Pro	missense_variant	Exon 6 of 7		XP_024302587.1
TMEM248	XM_024446820.2	c.809T>C	p.Leu270Pro	missense_variant	Exon 6 of 7		XP_024302588.1
TMEM248	XM_024446821.2	c.809T>C	p.Leu270Pro	missense_variant	Exon 6 of 7		XP_024302589.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM248	ENST00000341567.8	c.809T>C	p.Leu270Pro	missense_variant	Exon 6 of 7	1	NM_017994.5	ENSP00000340668.4
TMEM248	ENST00000433271.6	n.*13T>C		non_coding_transcript_exon_variant	Exon 5 of 6	1		ENSP00000405558.2
TMEM248	ENST00000433271.6	n.*13T>C		3_prime_UTR_variant	Exon 5 of 6	1		ENSP00000405558.2

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

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.809T>C (p.L270P) alteration is located in exon 6 (coding exon 5) of the TMEM248 gene. This alteration results from a T to C substitution at nucleotide position 809, causing the leucine (L) at amino acid position 270 to be replaced by a proline (P). 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	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.90	L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.71		Loss of catalytic residue at L270 (P = 0.0064);
MVP		0.13
MPC		1.3
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-66418241;