chr8-144513286-C-T

Variant names:

• chr8-144513286-C-T
• rs34293591
• NM_004260.4:c.2395G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004260.4(RECQL4):​c.2395G>A​(p.Val799Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,598,680 control chromosomes in the GnomAD database, including 704 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V799L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (29 hom., cov: 33)
  • Exomes 𝑓: 0.027 (675 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 2.27
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010660559).
• BP6: Variant 8-144513286-C-T is Benign according to our data. Variant chr8-144513286-C-T is described in ClinVar as Benign. ClinVar VariationId is 135138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0172 (2613/152246) while in subpopulation NFE AF = 0.0282 (1919/67988). AF 95% confidence interval is 0.0272. There are 29 homozygotes in GnomAd4. There are 1211 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AR,AD 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.2395G>A	p.Val799Met	missense	Exon 14 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.2395G>A	p.Val799Met	missense	Exon 14 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2395G>A	p.Val799Met	missense	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.2395G>A	p.Val799Met	missense	Exon 14 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.1324G>A	p.Val442Met	missense	Exon 13 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.2302G>A	p.Val768Met	missense	Exon 14 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2612 AN: 152128 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0242

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0282

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.0162 AC: 3646 AN: 225518 AF XY: 0.0160

Gnomad AFR exome AF: 0.00455

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0000571

Gnomad FIN exome AF: 0.0233

Gnomad NFE exome AF: 0.0259

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0268 AC: 38695 AN: 1446434 Hom.: 675 Cov.: 50 AF XY: 0.0257 AC XY: 18493 AN XY: 719970

African (AFR) AF: 0.00452 AC: 151 AN: 33444

American (AMR) AF: 0.0113 AC: 505 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.00196 AC: 51 AN: 26034

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39638

South Asian (SAS) AF: 0.00392 AC: 337 AN: 86008

European-Finnish (FIN) AF: 0.0230 AC: 918 AN: 39992

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5734

European-Non Finnish (NFE) AF: 0.0318 AC: 35344 AN: 1110936

Other (OTH) AF: 0.0230 AC: 1380 AN: 60130

GnomAD4 genome AF: 0.0172 AC: 2613 AN: 152246 Hom.: 29 Cov.: 33 AF XY: 0.0163 AC XY: 1211 AN XY: 74430

African (AFR) AF: 0.00522 AC: 217 AN: 41562

American (AMR) AF: 0.0107 AC: 163 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4826

European-Finnish (FIN) AF: 0.0242 AC: 257 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0282 AC: 1919 AN: 67988

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.0222 Hom.: 142

Bravo AF: 0.0162

TwinsUK AF: 0.0262 AC: 97

ALSPAC AF: 0.0254 AC: 98

ESP6500AA AF: 0.00537 AC: 21

ESP6500EA AF: 0.0226 AC: 186

ExAC AF: 0.0158 AC: 1883

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (3)
-	-	1	Baller-Gerold syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Rapadilino syndrome (1)
-	-	1	Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.011	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.3
PrimateAI	Uncertain	0.59	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.75
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.56
Mutation Taster		=90/10	polymorphism (auto)

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: rs34293591; hg19: chr8-145738669; COSMIC: COSV107348431;