15-90782869-C-T

Variant names:

• chr15-90782869-C-T
• rs2227935
• NM_000057.4:c.2603C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000057.4(BLM):​c.2603C>T​(p.Pro868Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0661 in 1,612,548 control chromosomes in the GnomAD database, including 3,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P868R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.065 (351 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3633 hom.)
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:20 O:1
• Conservation: PhyloP100: 5.73
• Publications: 29 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

ENSG00000300894 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009349495).
• BP6: Variant 15-90782869-C-T is Benign according to our data. Variant chr15-90782869-C-T is described in ClinVar as Benign. ClinVar VariationId is 92393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0673 is higher than 0.05.

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.2603C>T	p.Pro868Leu	missense	Exon 13 of 22	NP_000048.1	P54132
	BLM	NM_001287246.2		c.2603C>T	p.Pro868Leu	missense	Exon 14 of 23	NP_001274175.1	P54132
	BLM	NM_001287247.2		c.2603C>T	p.Pro868Leu	missense	Exon 13 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.2603C>T	p.Pro868Leu	missense	Exon 13 of 22	ENSP00000347232.3	P54132
	BLM	ENST00000560509.5	TSL:1	c.2603C>T	p.Pro868Leu	missense	Exon 13 of 20	ENSP00000454158.1	H0YNU5
	BLM	ENST00000559724.5	TSL:1	n.*1527C>T		non_coding_transcript_exon	Exon 13 of 22	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes AF: 0.0655 AC: 9956 AN: 151896 Hom.: 352 Cov.: 32

Gnomad AFR AF: 0.0664

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0482

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0689

Gnomad OTH AF: 0.0556

GnomAD2 exomes AF: 0.0556 AC: 13969 AN: 251184 AF XY: 0.0558

Gnomad AFR exome AF: 0.0675

Gnomad AMR exome AF: 0.0371

Gnomad ASJ exome AF: 0.0393

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0534

GnomAD4 exome AF: 0.0661 AC: 96587 AN: 1460534 Hom.: 3633 Cov.: 31 AF XY: 0.0654 AC XY: 47558 AN XY: 726652

African (AFR) AF: 0.0639 AC: 2138 AN: 33454

American (AMR) AF: 0.0388 AC: 1737 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0371 AC: 968 AN: 26124

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39676

South Asian (SAS) AF: 0.0443 AC: 3823 AN: 86228

European-Finnish (FIN) AF: 0.101 AC: 5382 AN: 53382

Middle Eastern (MID) AF: 0.0290 AC: 167 AN: 5766

European-Non Finnish (NFE) AF: 0.0708 AC: 78641 AN: 1110842

Other (OTH) AF: 0.0616 AC: 3719 AN: 60346

GnomAD4 genome AF: 0.0655 AC: 9956 AN: 152014 Hom.: 351 Cov.: 32 AF XY: 0.0656 AC XY: 4870 AN XY: 74280

African (AFR) AF: 0.0663 AC: 2748 AN: 41462

American (AMR) AF: 0.0552 AC: 844 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0309 AC: 107 AN: 3466

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.0478 AC: 230 AN: 4812

European-Finnish (FIN) AF: 0.110 AC: 1158 AN: 10518

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0689 AC: 4684 AN: 67980

Other (OTH) AF: 0.0550 AC: 116 AN: 2108

Alfa AF: 0.0630 Hom.: 899

Bravo AF: 0.0611

TwinsUK AF: 0.0725 AC: 269

ALSPAC AF: 0.0771 AC: 297

ESP6500AA AF: 0.0735 AC: 323

ESP6500EA AF: 0.0653 AC: 561

ExAC AF: 0.0556 AC: 6747

Asia WGS AF: 0.0210 AC: 74 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	Bloom syndrome (8)
-	-	4	not provided (4)
-	-	4	not specified (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	Hereditary disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.18
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.73	P
Vest4		0.25
MPC		0.46
ClinPred		0.061	T
GERP RS		5.5
Varity_R		0.39
gMVP		0.83
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs2227935; hg19: chr15-91326099;