rs756627

Variant names:

• chr8-144511903-G-A
• rs756627
• NM_004260.4:c.3393+8C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144511903-G-A
• chr8-144511903-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001413036.1(RECQL4):​c.3401C>T​(p.Ala1134Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,609,516 control chromosomes in the GnomAD database, including 175,591 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/11 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1134E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.39 (13393 hom., cov: 35)
  • Exomes 𝑓: 0.47 (162198 hom.)
• Consequence: RECQL4 NM_001413036.1 missense, splice_region
• Scores: Splicing: ADA: 0.00003801
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.00
• Publications: 33 publications found

Genes affected

RECQL4 (HGNC:9949): (RecQ like helicase 4) The protein encoded by this gene is a DNA helicase that belongs to the RecQ helicase family. DNA helicases unwind double-stranded DNA into single-stranded DNAs and may modulate chromosome segregation. This gene is predominantly expressed in thymus and testis. Mutations in this gene are associated with Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. [provided by RefSeq, Jan 2010]

RECQL4 Gene-Disease associations (from GenCC):

• Baller-Gerold syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• Rothmund-Thomson syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Rothmund-Thomson syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• osteosarcoma

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• rapadilino syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 27 uncertain in NM_001413036.1
• BP4: Computational evidence support a benign effect (MetaRNN=2.8563938E-5).
• BP6: Variant 8-144511903-G-A is Benign according to our data. Variant chr8-144511903-G-A is described in ClinVar as Benign. ClinVar VariationId is 94894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001413036.1. 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
	RECQL4	NM_004260.4	MANE Select	c.3393+8C>T		splice_region intron	N/A	NP_004251.4	O94761
	RECQL4	NM_001413036.1		c.3401C>T	p.Ala1134Val	missense splice_region	Exon 19 of 21	NP_001399965.1
	RECQL4	NM_001413019.1		c.3468+8C>T		splice_region intron	N/A	NP_001399948.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.3393+8C>T		splice_region intron	N/A	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.2322+8C>T		splice_region intron	N/A	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000531875.2	TSL:5	c.647C>T	p.Ala216Val	missense splice_region	Exon 4 of 6	ENSP00000477910.1	A0A087WTJ0

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58955 AN: 152096 Hom.: 13389 Cov.: 35

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.420

GnomAD2 exomes AF: 0.476 AC: 116530 AN: 244932 AF XY: 0.482

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.560

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.493

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.465

GnomAD4 exome AF: 0.467 AC: 680494 AN: 1457302 Hom.: 162198 Cov.: 49 AF XY: 0.471 AC XY: 341695 AN XY: 724980

African (AFR) AF: 0.124 AC: 4148 AN: 33472

American (AMR) AF: 0.549 AC: 24514 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 11465 AN: 26120

East Asian (EAS) AF: 0.443 AC: 17568 AN: 39684

South Asian (SAS) AF: 0.565 AC: 48748 AN: 86234

European-Finnish (FIN) AF: 0.494 AC: 24633 AN: 49912

Middle Eastern (MID) AF: 0.358 AC: 2062 AN: 5762

European-Non Finnish (NFE) AF: 0.468 AC: 520064 AN: 1111190

Other (OTH) AF: 0.453 AC: 27292 AN: 60288

GnomAD4 genome AF: 0.387 AC: 58965 AN: 152214 Hom.: 13393 Cov.: 35 AF XY: 0.395 AC XY: 29397 AN XY: 74408

African (AFR) AF: 0.139 AC: 5767 AN: 41556

American (AMR) AF: 0.507 AC: 7752 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1464 AN: 3472

East Asian (EAS) AF: 0.493 AC: 2550 AN: 5172

South Asian (SAS) AF: 0.587 AC: 2837 AN: 4830

European-Finnish (FIN) AF: 0.500 AC: 5297 AN: 10604

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.471 AC: 32049 AN: 67976

Other (OTH) AF: 0.418 AC: 885 AN: 2116

Alfa AF: 0.421 Hom.: 33435

Bravo AF: 0.375

TwinsUK AF: 0.457 AC: 1696

ALSPAC AF: 0.469 AC: 1806

ESP6500AA AF: 0.139 AC: 598

ESP6500EA AF: 0.457 AC: 3883

ExAC AF: 0.463 AC: 55704

Asia WGS AF: 0.529 AC: 1838 AN: 3478

EpiCase AF: 0.470

EpiControl AF: 0.471

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Baller-Gerold syndrome (2)
-	-	2	not provided (2)
-	-	1	Rapadilino syndrome (1)
-	-	1	Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.0
DANN	Benign	0.60
DEOGEN2	Benign	0.0024	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.000029	T
PhyloP100		1.0
Sift4G	Benign	0.30	T
GERP RS		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.10		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: rs756627; hg19: chr8-145737286; COSMIC: COSV56739629; COSMIC: COSV56739629;