22-23181122-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_004327.4(BCR):c.162C>T(p.Phe54=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,498,616 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (11 hom.)
• Consequence: BCR NM_004327.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.65

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 22-23181122-C-T is Benign according to our data. Variant chr22-23181122-C-T is described in ClinVar as [Benign]. Clinvar id is 719837.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00798 (1193/149506) while in subpopulation AFR AF= 0.027 (1116/41316). AF 95% confidence interval is 0.0257. There are 18 homozygotes in gnomad4. There are 548 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1184 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCR	NM_004327.4	c.162C>T	p.Phe54=	synonymous_variant	1/23	ENST00000305877.13
BCR	NM_021574.3	c.162C>T	p.Phe54=	synonymous_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCR	ENST00000305877.13	c.162C>T	p.Phe54=	synonymous_variant	1/23	1	NM_004327.4	P1
BCR	ENST00000359540.7	c.162C>T	p.Phe54=	synonymous_variant	1/22	1
BCR	ENST00000479188.5	n.129+1290C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00793 AC: 1184 AN: 149398 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00385

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000746

Gnomad OTH AF: 0.00679

GnomAD3 exomes AF: 0.00156 AC: 253 AN: 162246 Hom.: 0 AF XY: 0.00117 AC XY: 103 AN XY: 87964

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000107

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.000786 AC: 1061 AN: 1349110 Hom.: 11 Cov.: 30 AF XY: 0.000664 AC XY: 444 AN XY: 668458

Gnomad4 AFR exome AF: 0.0299

Gnomad4 AMR exome AF: 0.00214

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000308

Gnomad4 SAS exome AF: 0.0000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000400

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00798 AC: 1193 AN: 149506 Hom.: 18 Cov.: 32 AF XY: 0.00751 AC XY: 548 AN XY: 72938

Gnomad4 AFR AF: 0.0270

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000746

Gnomad4 OTH AF: 0.00672

Alfa AF: 0.00337 Hom.: 2

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	13
Dann	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs112539379; hg19: chr22-23523309;