8-144516055-C-T

Variant names:

• chr8-144516055-C-T
• rs374743591
• NM_004260.4:c.1064G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

The NM_004260.4(RECQL4):​c.1064G>A​(p.Arg355Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000321 in 1,612,646 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R355L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:1
• Conservation: PhyloP100: 0.376
• Publications: 9 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, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• osteosarcoma

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP5: Variant 8-144516055-C-T is Pathogenic according to our data. Variant chr8-144516055-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 407037.
• BP4: Computational evidence support a benign effect (MetaRNN=0.021392375). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000336 (491/1460294) while in subpopulation EAS AF = 0.0115 (455/39694). AF 95% confidence interval is 0.0106. There are 4 homozygotes in GnomAdExome4. There are 256 alleles in the male GnomAdExome4 subpopulation. Median coverage is 66. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 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.1064G>A	p.Arg355Gln	missense	Exon 5 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.1064G>A	p.Arg355Gln	missense	Exon 5 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.1064G>A	p.Arg355Gln	missense	Exon 5 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.1064G>A	p.Arg355Gln	missense	Exon 5 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.-8G>A		5_prime_UTR	Exon 4 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.1064G>A	p.Arg355Gln	missense	Exon 5 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000137 AC: 34 AN: 247884 AF XY: 0.000141

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00184

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000336 AC: 491 AN: 1460294 Hom.: 4 Cov.: 66 AF XY: 0.000352 AC XY: 256 AN XY: 726426

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0115 AC: 455 AN: 39694

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111790

Other (OTH) AF: 0.0000994 AC: 6 AN: 60350

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74496

African (AFR) AF: 0.000120 AC: 5 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000591 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Baller-Gerold syndrome (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Ovarian cancer (1)
-	-	1	RECQL4-related disorder (1)
-	1	-	Rothmund-Thomson syndrome;C0265308:Baller-Gerold syndrome;C1849453:Rapadilino syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.75
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.021	T
PhyloP100		0.38
PrimateAI	Benign	0.38	T
Sift4G	Uncertain	0.025	D
Polyphen		0.94	P
Vest4		0.43
MVP		0.72
GERP RS		4.4
PromoterAI		0.0080	Neutral
Varity_R		0.11
gMVP		0.27
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs374743591; hg19: chr8-145741439; COSMIC: COSV52877601; COSMIC: COSV52877601;