NM_004260.4:c.2238G>A

Variant names:

• chr8-144513443-C-T
• rs35215952
• NM_004260.4:c.2238G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004260.4(RECQL4):​c.2238G>A​(p.Ala746Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,609,742 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A746A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0094 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (28 hom.)
• Consequence: RECQL4 NM_004260.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.18
• Publications: 5 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

ENSG00000265393 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-144513443-C-T is Benign according to our data. Variant chr8-144513443-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00939 (1431/152350) while in subpopulation AFR AF = 0.027 (1124/41568). AF 95% confidence interval is 0.0257. There are 10 homozygotes in GnomAd4. There are 684 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004260.4. 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
	RECQL4	NM_004260.4	MANE Select	c.2238G>A	p.Ala746Ala	synonymous	Exon 14 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.2238G>A	p.Ala746Ala	synonymous	Exon 14 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2238G>A	p.Ala746Ala	synonymous	Exon 14 of 21	NP_001399965.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.2238G>A	p.Ala746Ala	synonymous	Exon 14 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.1167G>A	p.Ala389Ala	synonymous	Exon 13 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.2145G>A	p.Ala715Ala	synonymous	Exon 14 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00930 AC: 1416 AN: 152232 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00342 AC: 830 AN: 242480 AF XY: 0.00309

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.00293

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000104

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.00453

GnomAD4 exome AF: 0.00310 AC: 4515 AN: 1457392 Hom.: 28 Cov.: 47 AF XY: 0.00295 AC XY: 2142 AN XY: 725182

African (AFR) AF: 0.0279 AC: 933 AN: 33470

American (AMR) AF: 0.00528 AC: 236 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000360 AC: 31 AN: 86228

European-Finnish (FIN) AF: 0.000223 AC: 11 AN: 49364

Middle Eastern (MID) AF: 0.00624 AC: 36 AN: 5766

European-Non Finnish (NFE) AF: 0.00259 AC: 2879 AN: 1111756

Other (OTH) AF: 0.00471 AC: 284 AN: 60322

GnomAD4 genome AF: 0.00939 AC: 1431 AN: 152350 Hom.: 10 Cov.: 33 AF XY: 0.00918 AC XY: 684 AN XY: 74504

African (AFR) AF: 0.0270 AC: 1124 AN: 41568

American (AMR) AF: 0.00653 AC: 100 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00231 AC: 157 AN: 68038

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.00524 Hom.: 3

Bravo AF: 0.0107

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00308

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Baller-Gerold syndrome (1)
-	-	1	not specified (1)
-	-	1	Rapadilino syndrome (1)
-	-	1	RECQL4-related disorder (1)
-	-	1	Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.21
DANN	Benign	0.87
PhyloP100		-2.2
Mutation Taster		=99/1	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: rs35215952; hg19: chr8-145738827; COSMIC: COSV104618491;