chr4-83482207-T-C

Variant names:

• chr4-83482207-T-C
• rs201948472
• NM_139076.3:c.125A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_139076.3(ABRAXAS1):​c.125A>G​(p.Lys42Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000298 in 1,612,592 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K42K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: ABRAXAS1 NM_139076.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.85
• Publications: 5 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03453189).
• BP6: Variant 4-83482207-T-C is Benign according to our data. Variant chr4-83482207-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128218.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139076.3. 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
	ABRAXAS1	NM_139076.3	MANE Select	c.125A>G	p.Lys42Arg	missense	Exon 2 of 9	NP_620775.2
	ABRAXAS1	NM_001345962.2		c.-136A>G		5_prime_UTR	Exon 2 of 8	NP_001332891.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABRAXAS1	ENST00000321945.12	TSL:1 MANE Select	c.125A>G	p.Lys42Arg	missense	Exon 2 of 9	ENSP00000369857.3
	ABRAXAS1	ENST00000515303.2	TSL:1	c.-27A>G		5_prime_UTR	Exon 2 of 3	ENSP00000421068.1
	ABRAXAS1	ENST00000856950.1		c.125A>G	p.Lys42Arg	missense	Exon 2 of 9	ENSP00000527009.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000303 AC: 75 AN: 247884 AF XY: 0.000253

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000460

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000301 AC: 440 AN: 1460356 Hom.: 0 Cov.: 29 AF XY: 0.000299 AC XY: 217 AN XY: 726526

African (AFR) AF: 0.0000299 AC: 1 AN: 33448

American (AMR) AF: 0.0000899 AC: 4 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.00218 AC: 57 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 85980

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 53038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000321 AC: 357 AN: 1111526

Other (OTH) AF: 0.000315 AC: 19 AN: 60338

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.000323 AC XY: 24 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000492 Hom.: 0

Bravo AF: 0.000287

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000224 AC: 27

EpiCase AF: 0.000983

EpiControl AF: 0.000534

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0029	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.91	T
PhyloP100		3.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.081
Sift	Benign	0.17	T
Sift4G	Benign	0.21	T
Polyphen		0.99	D
Vest4		0.36
MVP		0.38
MPC		0.15
ClinPred		0.12	T
GERP RS		4.3
Varity_R		0.060
gMVP		0.46
Mutation Taster		=284/16	polymorphism

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: rs201948472; hg19: chr4-84403360;