16-1827422-A-C

Position:

• chr16-1827422-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031208.4(FAHD1):​c.184A>C​(p.Thr62Pro) 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 benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAHD1 NM_031208.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

Genes affected

FAHD1 (HGNC:14169): (fumarylacetoacetate hydrolase domain containing 1) Enables acetylpyruvate hydrolase activity; fumarylpyruvate hydrolase activity; and oxaloacetate decarboxylase activity. Located in cytosol; mitochondrion; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35119703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAHD1	NM_031208.4	c.184A>C	p.Thr62Pro	missense_variant	1/1	ENST00000427358.5	NP_112485.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAHD1	ENST00000427358.5	c.184A>C	p.Thr62Pro	missense_variant	1/1		NM_031208.4	ENSP00000398053	P1
FAHD1	ENST00000382668.8	c.184A>C	p.Thr62Pro	missense_variant	1/2	1		ENSP00000372114
FAHD1	ENST00000382666.6	c.184A>C	p.Thr62Pro	missense_variant	1/3	2		ENSP00000372112

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Dec 16, 2023

The c.193A>C (p.T65P) alteration is located in exon 1 (coding exon 1) of the FAHD1 gene. This alteration results from a A to C substitution at nucleotide position 193, causing the threonine (T) at amino acid position 65 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	0.59
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.47	T;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T;T;.;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	2.0	M;M;M;M
MutationTaster	Benign	0.73	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	N;N;N;.
REVEL	Uncertain	0.45
Sift	Benign	0.050	D;T;T;.
Sift4G	Benign	0.097	T;T;T;T
Polyphen		0.0090	B;B;.;.
Vest4		0.16
MutPred		0.57		Loss of phosphorylation at T65 (P = 0.0355);Loss of phosphorylation at T65 (P = 0.0355);Loss of phosphorylation at T65 (P = 0.0355);Loss of phosphorylation at T65 (P = 0.0355);
MVP		0.91
MPC		0.21
ClinPred		0.34	T
GERP RS		3.3
Varity_R		0.93
gMVP		0.85

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: chr16-1877423;