chr12-21501473-G-A

Variant names:

• chr12-21501473-G-A
• rs1061627
• NM_002907.4:c.-349C>T

Variant summary

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

The NM_002907.4(RECQL):​c.-349C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 161,314 control chromosomes in the GnomAD database, including 41,339 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (38125 hom., cov: 27)
  • Exomes 𝑓: 0.79 (3214 hom.)
• Consequence: RECQL NM_002907.4 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.00007014
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.25
• Publications: 21 publications found

Genes affected

RECQL (HGNC:9948): (RecQ like helicase) The protein encoded by this gene is a member of the RecQ DNA helicase family. DNA helicases are enzymes involved in various types of DNA repair, including mismatch repair, nucleotide excision repair and direct repair. The encoded protein is involved in the processing of Holliday junctions, the suppression of sister chromatid exchanges, telomere maintenance, and is required for genotoxic stress resistance. Defects in this gene have been associated with several types of cancer. [provided by RefSeq, Jan 2017]

RECQL Gene-Disease associations (from GenCC):

• RECON progeroid syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-21501473-G-A is Benign according to our data. Variant chr12-21501473-G-A is described in ClinVar as Benign. ClinVar VariationId is 679678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002907.4. 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
	RECQL	NM_002907.4	MANE Select	c.-349C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_002898.2
	RECQL	NM_002907.4	MANE Select	c.-349C>T		5_prime_UTR	Exon 1 of 15	NP_002898.2
	RECQL	NM_032941.3		c.-152C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_116559.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL	ENST00000444129.7	TSL:2 MANE Select	c.-349C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000416739.2
	RECQL	ENST00000421138.6	TSL:1	c.-152C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000395449.2
	RECQL	ENST00000444129.7	TSL:2 MANE Select	c.-349C>T		5_prime_UTR	Exon 1 of 15	ENSP00000416739.2

Frequencies

GnomAD3 genomes AF: 0.679 AC: 102673 AN: 151160 Hom.: 38107 Cov.: 27

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.711

Gnomad EAS AF: 0.972

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.858

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.668

GnomAD4 exome AF: 0.787 AC: 7902 AN: 10036 Hom.: 3214 Cov.: 0 AF XY: 0.794 AC XY: 4320 AN XY: 5440

African (AFR) AF: 0.320 AC: 123 AN: 384

American (AMR) AF: 0.796 AC: 323 AN: 406

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 191 AN: 280

East Asian (EAS) AF: 0.976 AC: 359 AN: 368

South Asian (SAS) AF: 0.901 AC: 1601 AN: 1776

European-Finnish (FIN) AF: 0.863 AC: 392 AN: 454

Middle Eastern (MID) AF: 0.375 AC: 15 AN: 40

European-Non Finnish (NFE) AF: 0.783 AC: 4520 AN: 5776

Other (OTH) AF: 0.685 AC: 378 AN: 552

GnomAD4 genome AF: 0.679 AC: 102732 AN: 151278 Hom.: 38125 Cov.: 27 AF XY: 0.690 AC XY: 50949 AN XY: 73886

African (AFR) AF: 0.361 AC: 14850 AN: 41146

American (AMR) AF: 0.764 AC: 11625 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 2468 AN: 3472

East Asian (EAS) AF: 0.972 AC: 4887 AN: 5028

South Asian (SAS) AF: 0.875 AC: 4151 AN: 4742

European-Finnish (FIN) AF: 0.858 AC: 9040 AN: 10532

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53529 AN: 67836

Other (OTH) AF: 0.671 AC: 1411 AN: 2102

Alfa AF: 0.747 Hom.: 131162

Bravo AF: 0.656

Asia WGS AF: 0.867 AC: 3011 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.4
DANN	Benign	0.81
PhyloP100		-4.2
PromoterAI		-0.013	Neutral
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000070
dbscSNV1_RF	Benign	0.0080
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: rs1061627; hg19: chr12-21654407;