chr8-144513135-C-T

Variant names:

• chr8-144513135-C-T
• rs368611522
• NM_004260.4:c.2467G>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.2467G>A​(p.Glu823Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,555,340 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 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. E823G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00014 (2 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2 O:1
• Conservation: PhyloP100: 0.134
• Publications: 6 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020927489).
• BP6: Variant 8-144513135-C-T is Benign according to our data. Variant chr8-144513135-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135141.
• BS2: High Homozygotes in GnomAdExome4 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.2467G>A	p.Glu823Lys	missense	Exon 15 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.2467G>A	p.Glu823Lys	missense	Exon 15 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2467G>A	p.Glu823Lys	missense	Exon 15 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.2467G>A	p.Glu823Lys	missense	Exon 15 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.1396G>A	p.Glu466Lys	missense	Exon 14 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.2374G>A	p.Glu792Lys	missense	Exon 15 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 22 AN: 146134 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000215

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000213 AC: 43 AN: 201436 AF XY: 0.000202

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00247

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000110

Gnomad OTH exome AF: 0.000400

GnomAD4 exome AF: 0.000144 AC: 203 AN: 1409108 Hom.: 2 Cov.: 66 AF XY: 0.000144 AC XY: 100 AN XY: 694024

African (AFR) AF: 0.00 AC: 0 AN: 32578

American (AMR) AF: 0.000218 AC: 9 AN: 41306

Ashkenazi Jewish (ASJ) AF: 0.00308 AC: 71 AN: 23078

East Asian (EAS) AF: 0.00 AC: 0 AN: 38852

South Asian (SAS) AF: 0.000204 AC: 16 AN: 78382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5510

European-Non Finnish (NFE) AF: 0.0000840 AC: 91 AN: 1083722

Other (OTH) AF: 0.000275 AC: 16 AN: 58094

GnomAD4 genome AF: 0.000150 AC: 22 AN: 146232 Hom.: 0 Cov.: 34 AF XY: 0.000156 AC XY: 11 AN XY: 70694

African (AFR) AF: 0.000101 AC: 4 AN: 39600

American (AMR) AF: 0.000215 AC: 3 AN: 13978

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 7 AN: 3446

East Asian (EAS) AF: 0.000204 AC: 1 AN: 4914

South Asian (SAS) AF: 0.00 AC: 0 AN: 4634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.000104 AC: 7 AN: 67200

Other (OTH) AF: 0.00 AC: 0 AN: 2028

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000185

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000365 AC: 3

ExAC AF: 0.000160 AC: 19

ClinVar

ClinVar submissions

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	-	not specified (2)
-	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	0.095
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.6
DANN	Benign	0.75
DEOGEN2	Benign	0.018	T
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.021	T
MutationAssessor	Benign	0.080	N
PhyloP100		0.13
PrimateAI	Benign	0.37	T
Sift4G	Benign	0.80	T
Polyphen		0.23	B
Vest4		0.22
MVP		0.74
GERP RS		2.1
PromoterAI		0.0097	Neutral
Varity_R		0.12
gMVP		0.58
Mutation Taster		=99/1	polymorphism

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: rs368611522; hg19: chr8-145738518; COSMIC: COSV52878022; COSMIC: COSV52878022;