chr15-37951188-T-C

Position:

• chr15-37951188-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152453.4(TMCO5A):​c.821T>C​(p.Phe274Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMCO5A NM_152453.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.42

Genes affected

TMCO5A (HGNC:28558): (transmembrane and coiled-coil domains 5A) Predicted to be located in membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16612434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMCO5A	NM_152453.4	c.821T>C	p.Phe274Ser	missense_variant	12/12	ENST00000319669.5	NP_689666.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMCO5A	ENST00000319669.5	c.821T>C	p.Phe274Ser	missense_variant	12/12	1	NM_152453.4	ENSP00000327234	P1
TMCO5A	ENST00000559502.5	c.668+3492T>C		intron_variant		2		ENSP00000454112
TMCO5A	ENST00000560653.5	c.*261T>C		3_prime_UTR_variant, NMD_transcript_variant	12/12	5		ENSP00000453561

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461600 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

May 16, 2023

The c.821T>C (p.F274S) alteration is located in exon 11 (coding exon 10) of the TMCO5A gene. This alteration results from a T to C substitution at nucleotide position 821, causing the phenylalanine (F) at amino acid position 274 to be replaced by a serine (S). 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	0.34
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.056
Sift	Benign	0.089	T
Sift4G	Benign	0.082	T
Polyphen		0.32	B
Vest4		0.29
MutPred		0.43		Gain of catalytic residue at F274 (P = 0.0245);
MVP		0.32
MPC		0.22
ClinPred		0.59	D
GERP RS		4.6
Varity_R		0.12
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-38243389;