5-119634421-G-A

Variant names:

• chr5-119634421-G-A
• NM_001367956.1:c.673G>A

Variant summary

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

The NM_001367956.1(FAM170A):​c.673G>A​(p.Glu225Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FAM170A NM_001367956.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33212575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM170A	NM_001367956.1	c.673G>A	p.Glu225Lys	missense_variant	Exon 3 of 5	ENST00000695508.1	NP_001354885.1
FAM170A	NM_182761.4	c.673G>A	p.Glu225Lys	missense_variant	Exon 3 of 5		NP_877438.2
FAM170A	NM_001163991.2	c.532G>A	p.Glu178Lys	missense_variant	Exon 2 of 4		NP_001157463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM170A	ENST00000695508.1	c.673G>A	p.Glu225Lys	missense_variant	Exon 3 of 5		NM_001367956.1	ENSP00000511971.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

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: 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

Mar 23, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.673G>A (p.E225K) alteration is located in exon 3 (coding exon 3) of the FAM170A gene. This alteration results from a G to A substitution at nucleotide position 673, causing the glutamic acid (E) at amino acid position 225 to be replaced by a lysine (K). 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	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0071	.;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;M
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.2	.;.;N
REVEL	Benign	0.046
Sift	Uncertain	0.026	.;.;D
Sift4G	Uncertain	0.033	D;D;D
Polyphen		0.97	.;.;D
Vest4		0.59
MutPred		0.24		Gain of MoRF binding (P = 0.0021);.;Gain of MoRF binding (P = 0.0021);
MVP		0.030
ClinPred		0.87	D
GERP RS		2.1
Varity_R		0.068
gMVP		0.16

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: chr5-118970116; COSMIC: COSV58927841;