15-90794249-G-A

Variant names:

• chr15-90794249-G-A
• rs2227933
• NM_000057.4:c.3102G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000057.4(BLM):​c.3102G>A​(p.Thr1034Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,604,120 control chromosomes in the GnomAD database, including 24,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1034T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2317 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21983 hom.)
• Consequence: BLM NM_000057.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.60
• Publications: 26 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 15-90794249-G-A is Benign according to our data. Variant chr15-90794249-G-A is described in ClinVar as Benign. ClinVar VariationId is 92394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.184 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.3102G>A	p.Thr1034Thr	synonymous	Exon 16 of 22	NP_000048.1	P54132
	BLM	NM_001287246.2		c.3102G>A	p.Thr1034Thr	synonymous	Exon 17 of 23	NP_001274175.1	P54132
	BLM	NM_001287247.2		c.3102G>A	p.Thr1034Thr	synonymous	Exon 16 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.3102G>A	p.Thr1034Thr	synonymous	Exon 16 of 22	ENSP00000347232.3	P54132
	BLM	ENST00000560509.5	TSL:1	c.3102G>A	p.Thr1034Thr	synonymous	Exon 16 of 20	ENSP00000454158.1	H0YNU5
	BLM	ENST00000559724.5	TSL:1	n.*2026G>A		non_coding_transcript_exon	Exon 16 of 22	ENSP00000453359.1	H0YLV8

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26159 AN: 151912 Hom.: 2317 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.0969

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.0915

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.162

GnomAD2 exomes AF: 0.156 AC: 38931 AN: 248854 AF XY: 0.154

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.0914

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.180

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.171 AC: 248636 AN: 1452090 Hom.: 21983 Cov.: 31 AF XY: 0.169 AC XY: 122093 AN XY: 722340

African (AFR) AF: 0.183 AC: 6084 AN: 33302

American (AMR) AF: 0.0963 AC: 4267 AN: 44324

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 4298 AN: 25996

East Asian (EAS) AF: 0.174 AC: 6824 AN: 39258

South Asian (SAS) AF: 0.0885 AC: 7479 AN: 84540

European-Finnish (FIN) AF: 0.147 AC: 7790 AN: 53090

Middle Eastern (MID) AF: 0.141 AC: 811 AN: 5742

European-Non Finnish (NFE) AF: 0.182 AC: 201089 AN: 1105902

Other (OTH) AF: 0.167 AC: 9994 AN: 59936

GnomAD4 genome AF: 0.172 AC: 26182 AN: 152030 Hom.: 2317 Cov.: 32 AF XY: 0.168 AC XY: 12453 AN XY: 74328

African (AFR) AF: 0.186 AC: 7697 AN: 41462

American (AMR) AF: 0.117 AC: 1785 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 595 AN: 3472

East Asian (EAS) AF: 0.178 AC: 922 AN: 5166

South Asian (SAS) AF: 0.0925 AC: 446 AN: 4824

European-Finnish (FIN) AF: 0.147 AC: 1543 AN: 10524

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12718 AN: 67978

Other (OTH) AF: 0.162 AC: 342 AN: 2112

Alfa AF: 0.175 Hom.: 4963

Bravo AF: 0.170

Asia WGS AF: 0.139 AC: 484 AN: 3468

ClinVar

ClinVar submissions

Significance: 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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.2
DANN	Benign	0.62
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs2227933; hg19: chr15-91337479; COSMIC: COSV61922650;