rs35886055

Variant names:

• chr15-90749687-A-G
• rs35886055
• NM_000057.4:c.419A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000057.4(BLM):​c.419A>G​(p.Glu140Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,614,162 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E140E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0088 (27 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (29 hom.)
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 3.36
• Publications: 12 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Genomics England PanelApp, ClinGen, Laboratory for Molecular Medicine
• osteosarcoma

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004220754).
• BP6: Variant 15-90749687-A-G is Benign according to our data. Variant chr15-90749687-A-G is described in ClinVar as Benign. ClinVar VariationId is 133708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00883 (1345/152314) while in subpopulation AFR AF = 0.0308 (1282/41562). AF 95% confidence interval is 0.0294. There are 27 homozygotes in GnomAd4. There are 656 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	NM_000057.4	MANE Select	c.419A>G	p.Glu140Gly	missense	Exon 3 of 22	NP_000048.1	P54132
	BLM	NM_001287246.2		c.419A>G	p.Glu140Gly	missense	Exon 4 of 23	NP_001274175.1	P54132
	BLM	NM_001287247.2		c.419A>G	p.Glu140Gly	missense	Exon 3 of 20	NP_001274176.1	H0YNU5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	ENST00000355112.8	TSL:1 MANE Select	c.419A>G	p.Glu140Gly	missense	Exon 3 of 22	ENSP00000347232.3	P54132
	BLM	ENST00000560509.5	TSL:1	c.419A>G	p.Glu140Gly	missense	Exon 3 of 20	ENSP00000454158.1	H0YNU5
	BLM	ENST00000559724.5	TSL:1	n.419A>G		non_coding_transcript_exon	Exon 3 of 22	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes AF: 0.00882 AC: 1342 AN: 152196 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00230 AC: 577 AN: 251314 AF XY: 0.00183

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000950 AC: 1389 AN: 1461848 Hom.: 29 Cov.: 31 AF XY: 0.000854 AC XY: 621 AN XY: 727222

African (AFR) AF: 0.0346 AC: 1160 AN: 33478

American (AMR) AF: 0.00148 AC: 66 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53404

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1111998

Other (OTH) AF: 0.00156 AC: 94 AN: 60394

GnomAD4 genome AF: 0.00883 AC: 1345 AN: 152314 Hom.: 27 Cov.: 32 AF XY: 0.00881 AC XY: 656 AN XY: 74470

African (AFR) AF: 0.0308 AC: 1282 AN: 41562

American (AMR) AF: 0.00261 AC: 40 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68030

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00333 Hom.: 16

Bravo AF: 0.00965

ESP6500AA AF: 0.0330 AC: 145

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00290 AC: 352

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.071
Sift	Benign	0.26	T
Sift4G	Benign	0.49	T
Polyphen		0.68	P
Vest4		0.21
MVP		0.82
MPC		0.33
ClinPred		0.024	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.097
gMVP		0.11
Mutation Taster		=89/11	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: rs35886055; hg19: chr15-91292917; COSMIC: COSV104665711;