rs754324912

Variant names:

• chr8-144513110-T-C
• rs754324912
• NM_004260.4:c.2492A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-144513110-T-C
• chr8-144513110-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004260.4(RECQL4):​c.2492A>G​(p.His831Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000755 in 1,562,896 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H831P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000074 (1 hom., cov: 34)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.40
• Publications: 2 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, G2P, Orphanet
• Rothmund-Thomson syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Rothmund-Thomson syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• osteosarcoma

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ENSG00000265393 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.2492A>G	p.His831Arg	missense	Exon 15 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.2492A>G	p.His831Arg	missense	Exon 15 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2492A>G	p.His831Arg	missense	Exon 15 of 21	NP_001399965.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.2492A>G	p.His831Arg	missense	Exon 15 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.1421A>G	p.His474Arg	missense	Exon 14 of 20	ENSP00000483145.1
	RECQL4	ENST00000534626.6	TSL:5	c.662A>G	p.His221Arg	missense	Exon 6 of 8	ENSP00000477457.1

Frequencies

GnomAD3 genomes AF: 0.0000739 AC: 11 AN: 148770 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000535

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000202

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000714 AC: 15 AN: 210102 AF XY: 0.0000791

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000138

Gnomad OTH exome AF: 0.000193

GnomAD4 exome AF: 0.0000757 AC: 107 AN: 1414126 Hom.: 0 Cov.: 66 AF XY: 0.0000831 AC XY: 58 AN XY: 697848

African (AFR) AF: 0.00 AC: 0 AN: 32618

American (AMR) AF: 0.0000960 AC: 4 AN: 41646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23446

East Asian (EAS) AF: 0.00 AC: 0 AN: 38472

South Asian (SAS) AF: 0.00 AC: 0 AN: 80102

European-Finnish (FIN) AF: 0.0000407 AC: 2 AN: 49146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 0.0000903 AC: 98 AN: 1084966

Other (OTH) AF: 0.0000516 AC: 3 AN: 58154

GnomAD4 genome AF: 0.0000739 AC: 11 AN: 148770 Hom.: 1 Cov.: 34 AF XY: 0.000124 AC XY: 9 AN XY: 72444

African (AFR) AF: 0.00 AC: 0 AN: 40608

American (AMR) AF: 0.000535 AC: 8 AN: 14942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 4876

South Asian (SAS) AF: 0.00 AC: 0 AN: 4598

European-Finnish (FIN) AF: 0.000202 AC: 2 AN: 9900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67158

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000418 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Rothmund-Thomson syndrome type 2 (2)
-	1	-	Baller-Gerold syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	20
DANN	Benign	0.69
DEOGEN2	Benign	0.097	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.59	D
MutationAssessor	Benign	1.0	L
PhyloP100		2.4
PrimateAI	Uncertain	0.58	T
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.65
MVP		0.67
GERP RS		5.1
PromoterAI		0.084	Neutral
Varity_R		0.20
gMVP		0.73
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs754324912; hg19: chr8-145738493; COSMIC: COSV105873934;