chr8-144514032-C-T

Variant names:

• chr8-144514032-C-T
• rs61754061
• NM_004260.4:c.1954G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004260.4(RECQL4):​c.1954G>A​(p.Val652Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00418 in 1,575,652 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 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. V652A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0043 (11 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: 3.10
• Publications: 12 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012555599).
• BP6: Variant 8-144514032-C-T is Benign according to our data. Variant chr8-144514032-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193964.
• BS2: High Homozygotes in GnomAd4 at 2 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.1954G>A	p.Val652Met	missense	Exon 12 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.1954G>A	p.Val652Met	missense	Exon 12 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.1954G>A	p.Val652Met	missense	Exon 12 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.1954G>A	p.Val652Met	missense	Exon 12 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.883G>A	p.Val295Met	missense	Exon 11 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.1861G>A	p.Val621Met	missense	Exon 12 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 411 AN: 152048 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00243 AC: 442 AN: 182162 AF XY: 0.00217

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.000230

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00460

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.00434 AC: 6173 AN: 1423486 Hom.: 11 Cov.: 36 AF XY: 0.00427 AC XY: 3007 AN XY: 704976

African (AFR) AF: 0.00101 AC: 33 AN: 32544

American (AMR) AF: 0.00179 AC: 70 AN: 39046

Ashkenazi Jewish (ASJ) AF: 0.000314 AC: 8 AN: 25438

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37360

South Asian (SAS) AF: 0.000405 AC: 33 AN: 81538

European-Finnish (FIN) AF: 0.00157 AC: 77 AN: 49142

Middle Eastern (MID) AF: 0.000527 AC: 3 AN: 5698

European-Non Finnish (NFE) AF: 0.00529 AC: 5788 AN: 1093718

Other (OTH) AF: 0.00271 AC: 160 AN: 59002

GnomAD4 genome AF: 0.00270 AC: 411 AN: 152166 Hom.: 2 Cov.: 34 AF XY: 0.00230 AC XY: 171 AN XY: 74396

African (AFR) AF: 0.00108 AC: 45 AN: 41512

American (AMR) AF: 0.00144 AC: 22 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00475 AC: 323 AN: 67954

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00429 Hom.: 1

Bravo AF: 0.00276

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00166 AC: 7

ESP6500EA AF: 0.00464 AC: 39

ExAC AF: 0.00217 AC: 258

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	5	not provided (7)
-	-	2	Baller-Gerold syndrome (2)
-	-	2	not specified (2)
-	-	1	Hereditary cancer-predisposing syndrome (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
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.77
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.013	T
PhyloP100		3.1
PrimateAI	Uncertain	0.53	T
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.60
MVP		0.36
GERP RS		3.6
PromoterAI		-0.11	Neutral
Varity_R		0.068
gMVP		0.49
Mutation Taster		=89/11	polymorphism

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: rs61754061; hg19: chr8-145739416;