rs778994524

Variant names:

• chr15-90798284-A-G
• rs778994524
• NM_000057.4:c.3305A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000057.4(BLM):​c.3305A>G​(p.His1102Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1102Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.353
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04968503).

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.3305A>G	p.His1102Arg	missense	Exon 17 of 22	NP_000048.1
	BLM	NM_001287246.2		c.3305A>G	p.His1102Arg	missense	Exon 18 of 23	NP_001274175.1
	BLM	NM_001287247.2		c.3305A>G	p.His1102Arg	missense	Exon 17 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.3305A>G	p.His1102Arg	missense	Exon 17 of 22	ENSP00000347232.3
	BLM	ENST00000560509.5	TSL:1	c.3305A>G	p.His1102Arg	missense	Exon 17 of 20	ENSP00000454158.1
	BLM	ENST00000559724.5	TSL:1	n.*2229A>G		non_coding_transcript_exon	Exon 17 of 22	ENSP00000453359.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250748 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460544 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726574

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000224 AC: 1 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111234

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Bloom syndrome (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.51
DANN	Benign	0.49
DEOGEN2	Benign	0.089	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.35
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.028
Sift	Benign	0.63	T
Sift4G	Benign	0.66	T
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.42		Gain of MoRF binding (P = 0.0139)
MVP		0.61
MPC		0.11
ClinPred		0.0068	T
GERP RS		1.4
Varity_R		0.076
gMVP		0.58

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: rs778994524; hg19: chr15-91341514;