1-151847795-A-C

Position:

• chr1-151847795-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_182578.4(THEM5):​c.643T>G​(p.Tyr215Asp) variant causes a missense change involving the alteration of a non-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: 30)
• Consequence: THEM5 NM_182578.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

Genes affected

THEM5 (HGNC:26755): (thioesterase superfamily member 5) Enables palmitoyl-CoA hydrolase activity. Involved in long-chain fatty-acyl-CoA metabolic process. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

C2CD4D-AS1 (HGNC:54045): (C2CD4D and THEM5 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THEM5	NM_182578.4	c.643T>G	p.Tyr215Asp	missense_variant	5/6	ENST00000368817.10	NP_872384.2
C2CD4D-AS1	NR_024237.2	n.1031-2438A>C		intron_variant, non_coding_transcript_variant
THEM5	XM_011509421.2	c.576-381T>G		intron_variant			XP_011507723.1
C2CD4D-AS1	NR_152846.1	n.951-2438A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THEM5	ENST00000368817.10	c.643T>G	p.Tyr215Asp	missense_variant	5/6	1	NM_182578.4	ENSP00000357807	P1
C2CD4D-AS1	ENST00000434182.1	n.354-2438A>C		intron_variant, non_coding_transcript_variant		5
THEM5	ENST00000453881.2	c.223-381T>G		intron_variant		4		ENSP00000406809

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

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

Jul 26, 2022

The c.643T>G (p.Y215D) alteration is located in exon 5 (coding exon 5) of the THEM5 gene. This alteration results from a T to G substitution at nucleotide position 643, causing the tyrosine (Y) at amino acid position 215 to be replaced by an aspartic acid (D). 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	0.59
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.64	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.60		Gain of disorder (P = 0.0202);
MVP		0.35
MPC		0.50
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.94
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-151820271;