2-97085861-C-T

Position:

• chr2-97085861-C-T

Variant summary

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

The NM_001320848.2(FAHD2B):​c.523G>A​(p.Ala175Thr) variant causes a missense, splice region 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. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: FAHD2B NM_001320848.2 missense, splice_region
• Scores: Splicing: ADA: 0.4668
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

Genes affected

FAHD2B (HGNC:25318): (fumarylacetoacetate hydrolase domain containing 2B) Predicted to enable hydro-lyase activity. [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=0.24609265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAHD2B	NM_001320848.2	c.523G>A	p.Ala175Thr	missense_variant, splice_region_variant	6/9	ENST00000414820.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAHD2B	ENST00000414820.6	c.523G>A	p.Ala175Thr	missense_variant, splice_region_variant	6/9	5	NM_001320848.2	P1
FAHD2B	ENST00000272610.3	c.523G>A	p.Ala175Thr	missense_variant, splice_region_variant	5/8	1		P1
FAHD2B	ENST00000463096.5	n.728G>A		non_coding_transcript_exon_variant	3/5	5
FAHD2B	ENST00000474849.1	n.121-1584G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

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

Aug 09, 2021

The c.523G>A (p.A175T) alteration is located in exon 5 (coding exon 4) of the FAHD2B gene. This alteration results from a G to A substitution at nucleotide position 523, causing the alanine (A) at amino acid position 175 to be replaced by a threonine (T). 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	Benign	0.082
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.50	N
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.28	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.51	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.74	P;P
Vest4		0.14
MutPred		0.40		Gain of methylation at K171 (P = 0.0756);Gain of methylation at K171 (P = 0.0756);
MVP		0.90
MPC		1.4
ClinPred		0.57	D
GERP RS		0.62
Varity_R		0.030
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.47
dbscSNV1_RF	Benign	0.48
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: chr2-97751598; COSMIC: COSV99737979; COSMIC: COSV99737979;