rs2229035

Variant names:

• chr15-90794275-C-A
• rs2229035
• NM_000057.4:c.3128C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-90794275-C-A
• chr15-90794275-C-T

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.3128C>A​(p.Ala1043Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000665 in 1,606,918 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1043V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (6 hom.)
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 7.70
• Publications: 11 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

ENSG00000300894 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.014257282).
• BP6: Variant 15-90794275-C-A is Benign according to our data. Variant chr15-90794275-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136516.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 = 0.00385 (585/152116) while in subpopulation AFR AF = 0.0125 (517/41510). AF 95% confidence interval is 0.0116. There are 3 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD 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.3128C>A	p.Ala1043Asp	missense	Exon 16 of 22	NP_000048.1
	BLM	NM_001287246.2		c.3128C>A	p.Ala1043Asp	missense	Exon 17 of 23	NP_001274175.1
	BLM	NM_001287247.2		c.3128C>A	p.Ala1043Asp	missense	Exon 16 of 20	NP_001274176.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLM	ENST00000355112.8	TSL:1 MANE Select	c.3128C>A	p.Ala1043Asp	missense	Exon 16 of 22	ENSP00000347232.3
	BLM	ENST00000560509.5	TSL:1	c.3128C>A	p.Ala1043Asp	missense	Exon 16 of 20	ENSP00000454158.1
	BLM	ENST00000559724.5	TSL:1	n.*2052C>A		non_coding_transcript_exon	Exon 16 of 22	ENSP00000453359.1

Frequencies

GnomAD3 genomes AF: 0.00383 AC: 582 AN: 151998 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00361

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000877 AC: 219 AN: 249668 AF XY: 0.000578

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.000555

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.000332 AC: 483 AN: 1454802 Hom.: 6 Cov.: 31 AF XY: 0.000265 AC XY: 192 AN XY: 723562

African (AFR) AF: 0.0112 AC: 374 AN: 33388

American (AMR) AF: 0.000900 AC: 40 AN: 44428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39238

South Asian (SAS) AF: 0.00 AC: 0 AN: 84790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5744

European-Non Finnish (NFE) AF: 0.00000993 AC: 11 AN: 1108114

Other (OTH) AF: 0.000867 AC: 52 AN: 59998

GnomAD4 genome AF: 0.00385 AC: 585 AN: 152116 Hom.: 3 Cov.: 32 AF XY: 0.00366 AC XY: 272 AN XY: 74356

African (AFR) AF: 0.0125 AC: 517 AN: 41510

American (AMR) AF: 0.00360 AC: 55 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68004

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.000696 Hom.: 1

Bravo AF: 0.00480

ESP6500AA AF: 0.0105 AC: 46

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000997 AC: 121

Asia WGS AF: 0.000579 AC: 3 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Bloom syndrome (6)
-	-	4	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.34
Sift	Benign	0.59	T
Sift4G	Benign	0.85	T
Polyphen		0.034	B
Vest4		0.71
MVP		0.87
MPC		0.33
ClinPred		0.096	T
GERP RS		5.5
Varity_R		0.53
gMVP		0.83
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2229035; hg19: chr15-91337505;