15-90766979-A-G

Variant names:

• chr15-90766979-A-G
• rs142551229
• NM_000057.4:c.2263A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000057.4(BLM):​c.2263A>G​(p.Lys755Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000235 in 1,602,870 control chromosomes in the GnomAD database, including 2 homozygotes. 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. K755K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9 O:1
• Conservation: PhyloP100: 5.41
• Publications: 6 publications found

Genes affected

BLM (HGNC:1058): (BLM RecQ like helicase) The Bloom syndrome is an autosomal recessive disorder characterized by growth deficiency, microcephaly and immunodeficiency among others. It is caused by homozygous or compound heterozygous mutation in the gene encoding DNA helicase RecQ protein on chromosome 15q26. This Bloom-associated helicase unwinds a variety of DNA substrates including Holliday junction, and is involved in several pathways contributing to the maintenance of genome stability. Identification of pathogenic Bloom variants is required for heterozygote testing in at-risk families. [provided by RefSeq, May 2020]

BLM Gene-Disease associations (from GenCC):

• Bloom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet, Genomics England PanelApp, ClinGen
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01152724).
• BP6: Variant 15-90766979-A-G is Benign according to our data. Variant chr15-90766979-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133697.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00127 (194/152334) while in subpopulation AFR AF = 0.0045 (187/41574). AF 95% confidence interval is 0.00397. There are 1 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000057.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	NM_000057.4	MANE Select	c.2263A>G	p.Lys755Glu	missense	Exon 10 of 22	NP_000048.1
	BLM	NM_001287246.2		c.2263A>G	p.Lys755Glu	missense	Exon 11 of 23	NP_001274175.1
	BLM	NM_001287247.2		c.2263A>G	p.Lys755Glu	missense	Exon 10 of 20	NP_001274176.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	ENST00000355112.8	TSL:1 MANE Select	c.2263A>G	p.Lys755Glu	missense	Exon 10 of 22	ENSP00000347232.3
	BLM	ENST00000560509.5	TSL:1	c.2263A>G	p.Lys755Glu	missense	Exon 10 of 20	ENSP00000454158.1
	BLM	ENST00000559724.5	TSL:1	n.*1187A>G		non_coding_transcript_exon	Exon 10 of 22	ENSP00000453359.1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 194 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00451

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000280 AC: 70 AN: 249774 AF XY: 0.000207

Gnomad AFR exome AF: 0.00418

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1450536 Hom.: 1 Cov.: 29 AF XY: 0.000107 AC XY: 77 AN XY: 722012

African (AFR) AF: 0.00437 AC: 145 AN: 33204

American (AMR) AF: 0.0000897 AC: 4 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39468

South Asian (SAS) AF: 0.00 AC: 0 AN: 85384

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53316

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5734

European-Non Finnish (NFE) AF: 0.0000118 AC: 13 AN: 1102760

Other (OTH) AF: 0.000300 AC: 18 AN: 60038

GnomAD4 genome AF: 0.00127 AC: 194 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74512

African (AFR) AF: 0.00450 AC: 187 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000440 Hom.: 2

Bravo AF: 0.00166

ESP6500AA AF: 0.00432 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000338 AC: 41

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	-	2	Bloom syndrome (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not specified (3)
-	-	1	BLM-related disorder (1)
-	-	1	Hereditary cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		5.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.16
Sift	Benign	0.075	T
Sift4G	Uncertain	0.028	D
Polyphen		0.071	B
Vest4		0.46
MVP		0.68
MPC		0.55
ClinPred		0.055	T
GERP RS		5.7
Varity_R		0.66
gMVP		0.73
Mutation Taster		=64/36	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: rs142551229; hg19: chr15-91310209;