5-119632846-T-C

Variant names:

• chr5-119632846-T-C
• NM_001367956.1:c.169T>C

Variant summary

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

The NM_001367956.1(FAM170A):​c.169T>C​(p.Tyr57His) 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 1,460,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAM170A NM_001367956.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

Genes affected

FAM170A (HGNC:27963): (family with sequence similarity 170 member A) Predicted to enable DNA binding activity and metal ion binding activity. Involved in positive regulation of transcription, DNA-templated and transcription by RNA polymerase II. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

HSD17B4 (HGNC:5213): (hydroxysteroid 17-beta dehydrogenase 4) The protein encoded by this gene is a bifunctional enzyme that is involved in the peroxisomal beta-oxidation pathway for fatty acids. It also acts as a catalyst for the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids. Defects in this gene that affect the peroxisomal fatty acid beta-oxidation activity are a cause of D-bifunctional protein deficiency (DBPD). An apparent pseudogene of this gene is present on chromosome 8. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

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=0.21712887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM170A	NM_001367956.1	c.169T>C	p.Tyr57His	missense_variant	Exon 2 of 5	ENST00000695508.1	NP_001354885.1
FAM170A	NM_182761.4	c.169T>C	p.Tyr57His	missense_variant	Exon 2 of 5		NP_877438.2
FAM170A	NM_001163991.2	c.71-1114T>C		intron_variant	Intron 1 of 3		NP_001157463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM170A	ENST00000695508.1	c.169T>C	p.Tyr57His	missense_variant	Exon 2 of 5		NM_001367956.1	ENSP00000511971.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460678 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726528

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.169T>C (p.Y57H) alteration is located in exon 2 (coding exon 2) of the FAM170A gene. This alteration results from a T to C substitution at nucleotide position 169, causing the tyrosine (Y) at amino acid position 57 to be replaced by a histidine (H). 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	0.45
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	.;T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	.;N;D
REVEL	Benign	0.19
Sift	Uncertain	0.0060	.;D;D
Sift4G	Benign	0.15	T;T;D
Polyphen		1.0	.;D;D
Vest4		0.48
MutPred		0.28		Loss of phosphorylation at Y57 (P = 0.0561);Loss of phosphorylation at Y57 (P = 0.0561);Loss of phosphorylation at Y57 (P = 0.0561);
MVP		0.076
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.13
gMVP		0.13

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: chr5-118968541;