5-119634265-C-T

Variant names:

• chr5-119634265-C-T
• rs328694
• NM_001367956.1:c.517C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001367956.1(FAM170A):​c.517C>T​(p.Pro173Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,613,780 control chromosomes in the GnomAD database, including 162,208 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P173L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.42 (13716 hom., cov: 32)
  • Exomes 𝑓: 0.45 (148492 hom.)
• Consequence: FAM170A NM_001367956.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.996
• Publications: 35 publications found

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]

HSD17B4 Gene-Disease associations (from GenCC):

• d-bifunctional protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• Perrault syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Perrault syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3121963E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367956.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM170A	NM_001367956.1	MANE Select	c.517C>T	p.Pro173Ser	missense	Exon 3 of 5	NP_001354885.1	A1A519-1
	FAM170A	NM_182761.4		c.517C>T	p.Pro173Ser	missense	Exon 3 of 5	NP_877438.2	A1A519-2
	FAM170A	NM_001163991.2		c.376C>T	p.Pro126Ser	missense	Exon 2 of 4	NP_001157463.1	A1A519-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM170A	ENST00000695508.1	MANE Select	c.517C>T	p.Pro173Ser	missense	Exon 3 of 5	ENSP00000511971.1	A1A519-1
	FAM170A	ENST00000335286.10	TSL:1	c.517C>T	p.Pro173Ser	missense	Exon 3 of 5	ENSP00000334285.6	A1A519-2
	FAM170A	ENST00000379555.7	TSL:1	c.376C>T	p.Pro126Ser	missense	Exon 2 of 4	ENSP00000368873.3	A1A519-3

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64216 AN: 151882 Hom.: 13716 Cov.: 32

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.428

GnomAD2 exomes AF: 0.447 AC: 111530 AN: 249504 AF XY: 0.458

Gnomad AFR exome AF: 0.344

Gnomad AMR exome AF: 0.365

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.508

Gnomad FIN exome AF: 0.431

Gnomad NFE exome AF: 0.442

Gnomad OTH exome AF: 0.466

GnomAD4 exome AF: 0.448 AC: 654971 AN: 1461780 Hom.: 148492 Cov.: 53 AF XY: 0.453 AC XY: 329088 AN XY: 727198

African (AFR) AF: 0.345 AC: 11544 AN: 33474

American (AMR) AF: 0.372 AC: 16622 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 14445 AN: 26136

East Asian (EAS) AF: 0.555 AC: 22013 AN: 39698

South Asian (SAS) AF: 0.545 AC: 46989 AN: 86254

European-Finnish (FIN) AF: 0.426 AC: 22777 AN: 53420

Middle Eastern (MID) AF: 0.481 AC: 2773 AN: 5768

European-Non Finnish (NFE) AF: 0.441 AC: 489807 AN: 1111918

Other (OTH) AF: 0.464 AC: 28001 AN: 60390

GnomAD4 genome AF: 0.423 AC: 64244 AN: 152000 Hom.: 13716 Cov.: 32 AF XY: 0.429 AC XY: 31877 AN XY: 74296

African (AFR) AF: 0.348 AC: 14421 AN: 41464

American (AMR) AF: 0.446 AC: 6819 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 1930 AN: 3464

East Asian (EAS) AF: 0.510 AC: 2626 AN: 5146

South Asian (SAS) AF: 0.545 AC: 2621 AN: 4812

European-Finnish (FIN) AF: 0.439 AC: 4648 AN: 10576

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.439 AC: 29819 AN: 67938

Other (OTH) AF: 0.431 AC: 912 AN: 2116

Alfa AF: 0.439 Hom.: 55196

Bravo AF: 0.418

TwinsUK AF: 0.444 AC: 1645

ALSPAC AF: 0.438 AC: 1687

ESP6500AA AF: 0.341 AC: 1354

ESP6500EA AF: 0.445 AC: 3719

ExAC AF: 0.447 AC: 54024

Asia WGS AF: 0.526 AC: 1834 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.00013	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.093
Sift	Benign	0.27	T
Sift4G	Benign	0.40	T
Polyphen		1.0	D
Vest4		0.090
ClinPred		0.051	T
GERP RS		2.1
Varity_R		0.058
gMVP		0.22
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs328694; hg19: chr5-118969960; COSMIC: COSV58925239;