rs114513239

chr4-83463535-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_139076.3(ABRAXAS1):c.755G>A(p.Arg252Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,611,772 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: ABRAXAS1 NM_139076.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0180

Genes affected

ABRAXAS1 (HGNC:25829): (abraxas 1, BRCA1 A complex subunit) This gene encodes a protein that binds to the C-terminal repeats of breast cancer 1 (BRCA1) through a phospho-SXXF motif. The encoded protein recruits ubiquitin interaction motif containing 1 protein to BRCA1 protein and is required for DNA damage resistance, DNA repair, and cell cycle checkpoint control. Pseudogenes of this gene are found on chromosomes 3 and 8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

MRPS18C (HGNC:16633): (mitochondrial ribosomal protein S18C) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein that belongs to the ribosomal protein S18P family. The encoded protein is one of three that has significant sequence similarity to bacterial S18 proteins. The primary sequences of the three human mitochondrial S18 proteins are no more closely related to each other than they are to the prokaryotic S18 proteins. Pseudogenes corresponding to this gene are found on chromosomes 8p, 12p, 15q, and 22q. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009159774).
• BP6: Variant 4-83463535-C-T is Benign according to our data. Variant chr4-83463535-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128225.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABRAXAS1	NM_139076.3	c.755G>A	p.Arg252Gln	missense_variant	8/9	ENST00000321945.12
ABRAXAS1	NM_001345962.2	c.428G>A	p.Arg143Gln	missense_variant	7/8
ABRAXAS1	XR_001741334.3	n.919G>A		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABRAXAS1	ENST00000321945.12	c.755G>A	p.Arg252Gln	missense_variant	8/9	1	NM_139076.3	P1

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000703 AC: 176 AN: 250194 Hom.: 1 AF XY: 0.000724 AC XY: 98 AN XY: 135290

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00130 AC: 1904 AN: 1459464 Hom.: 3 Cov.: 29 AF XY: 0.00129 AC XY: 939 AN XY: 726042

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.000427

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000263

Gnomad4 NFE exome AF: 0.00164

Gnomad4 OTH exome AF: 0.000581

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000644 AC XY: 48 AN XY: 74484

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000842

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000725 AC: 88

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2014	FAM175A has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted FAM175A c.755G>A at the cDNA level, p.Arg252Gln (R252Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FAM175A Arg252Gln has been observed with an allele frequency of up to 0.1% in European Americans in the NHLBI Exome Sequencing Project. This variant is a semi-conservative substitution of a positive polar amino acid for a neutral polar one, altering a position that is highly variable throughout evolution and is located in the potential coiled-coil domain. In silico analyses predict this variant to have a benign effect on protein structure and function. At a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the FAM175A gene, remain unclear. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	ABRAXAS1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	2.1
Dann	Benign	0.79
DEOGEN2	Benign	0.0019	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.0092	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.18	T
PROVEAN	Benign	0.55	N;N
REVEL	Benign	0.025
Sift	Benign	0.36	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.0030	B;.
Vest4		0.093
MVP		0.25
MPC		0.12
ClinPred		0.0095	T
GERP RS		-3.4
Varity_R		0.019
gMVP		0.083

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

LitVar

Other links and lift over

dbSNP: rs114513239; hg19: chr4-84384688;