rs34735741

Variant names:

• chr8-144513266-G-A
• rs34735741
• NM_004260.4:c.2415C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144513266-G-A
• chr8-144513266-G-T
• chr8-144513266-G-C

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.2415C>T​(p.Ala805Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,593,724 control chromosomes in the GnomAD database, including 24 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. A805A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0056 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (17 hom.)
• Consequence: RECQL4 NM_004260.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.73
• Publications: 3 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=-0.75).
• BP6: Variant 8-144513266-G-A is Benign according to our data. Variant chr8-144513266-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00556 (845/152080) while in subpopulation AFR AF = 0.019 (787/41392). AF 95% confidence interval is 0.0179. There are 7 homozygotes in GnomAd4. There are 406 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.2415C>T	p.Ala805Ala	synonymous	Exon 14 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.2415C>T	p.Ala805Ala	synonymous	Exon 14 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2415C>T	p.Ala805Ala	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.2415C>T	p.Ala805Ala	synonymous	Exon 14 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.1344C>T	p.Ala448Ala	synonymous	Exon 13 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.2322C>T	p.Ala774Ala	synonymous	Exon 14 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00549 AC: 835 AN: 151962 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00149 AC: 327 AN: 219740 AF XY: 0.00123

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.000530

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.00126

GnomAD4 exome AF: 0.000685 AC: 987 AN: 1441644 Hom.: 17 Cov.: 48 AF XY: 0.000607 AC XY: 435 AN XY: 716902

African (AFR) AF: 0.0189 AC: 629 AN: 33262

American (AMR) AF: 0.00158 AC: 70 AN: 44296

Ashkenazi Jewish (ASJ) AF: 0.00100 AC: 26 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39448

South Asian (SAS) AF: 0.000187 AC: 16 AN: 85742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38880

Middle Eastern (MID) AF: 0.00302 AC: 17 AN: 5634

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1108516

Other (OTH) AF: 0.00182 AC: 109 AN: 59904

GnomAD4 genome AF: 0.00556 AC: 845 AN: 152080 Hom.: 7 Cov.: 33 AF XY: 0.00546 AC XY: 406 AN XY: 74352

African (AFR) AF: 0.0190 AC: 787 AN: 41392

American (AMR) AF: 0.00196 AC: 30 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67988

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00188 Hom.: 2

Bravo AF: 0.00623

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.5
DANN	Benign	0.91
PhyloP100		-5.7
PromoterAI		0.00010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34735741; hg19: chr8-145738649;