NM_004327.4:c.216G>A

Variant names:

• chr22-23181176-G-A
• rs1301518214
• NM_004327.4:c.216G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_004327.4(BCR):​c.216G>A​(p.Arg72Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000817 in 1,223,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R72R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: BCR NM_004327.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.872
• Publications: 0 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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP7: Synonymous conserved (PhyloP=-0.872 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004327.4. 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
	BCR	NM_004327.4	MANE Select	c.216G>A	p.Arg72Arg	synonymous	Exon 1 of 23	NP_004318.3
	BCR	NM_021574.3		c.216G>A	p.Arg72Arg	synonymous	Exon 1 of 22	NP_067585.2	P11274-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCR	ENST00000305877.13	TSL:1 MANE Select	c.216G>A	p.Arg72Arg	synonymous	Exon 1 of 23	ENSP00000303507.8	P11274-1
	BCR	ENST00000359540.7	TSL:1	c.216G>A	p.Arg72Arg	synonymous	Exon 1 of 22	ENSP00000352535.3	P11274-2
	BCR	ENST00000928588.1		c.216G>A	p.Arg72Arg	synonymous	Exon 1 of 23	ENSP00000598647.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.17e-7 AC: 1 AN: 1223346 Hom.: 0 Cov.: 30 AF XY: 0.00000167 AC XY: 1 AN XY: 599514

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26086

American (AMR) AF: 0.00 AC: 0 AN: 24774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19864

East Asian (EAS) AF: 0.0000368 AC: 1 AN: 27154

South Asian (SAS) AF: 0.00 AC: 0 AN: 55854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4954

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 974910

Other (OTH) AF: 0.00 AC: 0 AN: 47982

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.2
DANN	Benign	0.95
PhyloP100		-0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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: rs1301518214; hg19: chr22-23523363;