rs5996513

Variant names:

• chr22-23286888-C-T
• rs5996513
• NM_004327.4:c.2407-271C>T

Variant summary

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

The NM_004327.4(BCR):​c.2407-271C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 152,284 control chromosomes in the GnomAD database, including 536 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.052 (536 hom., cov: 33)
• Consequence: BCR NM_004327.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.607
• Publications: 3 publications found

Genes affected

BCR (HGNC:1014): (BCR activator of RhoGEF and GTPase) A reciprocal translocation between chromosomes 22 and 9 produces the Philadelphia chromosome, which is often found in patients with chronic myelogenous leukemia. The chromosome 22 breakpoint for this translocation is located within the BCR gene. The translocation produces a fusion protein which is encoded by sequence from both BCR and ABL, the gene at the chromosome 9 breakpoint. Although the BCR-ABL fusion protein has been extensively studied, the function of the normal BCR gene product is not clear. The unregulated tyrosine kinase activity of BCR-ABL1 contributes to the immortality of leukaemic cells. The BCR protein has serine/threonine kinase activity and is a GTPase-activating protein for p21rac and other kinases. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2020]

ENSG00000296232 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCR	NM_004327.4	c.2407-271C>T		intron_variant	Intron 10 of 22	ENST00000305877.13	NP_004318.3
BCR	NM_021574.3	c.2407-271C>T		intron_variant	Intron 10 of 21		NP_067585.2
LOC107985554	XR_001755448.2	n.316-115G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCR	ENST00000305877.13	c.2407-271C>T		intron_variant	Intron 10 of 22	1	NM_004327.4	ENSP00000303507.8

Frequencies

GnomAD3 genomes AF: 0.0514 AC: 7825 AN: 152166 Hom.: 526 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00735

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0425

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0518 AC: 7884 AN: 152284 Hom.: 536 Cov.: 33 AF XY: 0.0521 AC XY: 3883 AN XY: 74462

African (AFR) AF: 0.143 AC: 5934 AN: 41528

American (AMR) AF: 0.102 AC: 1561 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.0154 AC: 80 AN: 5186

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4820

European-Finnish (FIN) AF: 0.00735 AC: 78 AN: 10616

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68042

Other (OTH) AF: 0.0449 AC: 95 AN: 2114

Alfa AF: 0.0223 Hom.: 260

Bravo AF: 0.0632

Asia WGS AF: 0.0400 AC: 139 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.87
DANN	Benign	0.65
PhyloP100		-0.61
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: rs5996513; hg19: chr22-23629075;