8-144515803-C-T

Variant names:

• chr8-144515803-C-T
• rs117670586
• NM_004260.4:c.1219G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004260.4(RECQL4):​c.1219G>A​(p.Glu407Lys) 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 1,612,704 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E407A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 2.98
• 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, 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.093945086).

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.1219G>A	p.Glu407Lys	missense	Exon 6 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.1219G>A	p.Glu407Lys	missense	Exon 6 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.1219G>A	p.Glu407Lys	missense	Exon 6 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.1219G>A	p.Glu407Lys	missense	Exon 6 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.148G>A	p.Glu50Lys	missense	Exon 5 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000887977.1		c.1219G>A	p.Glu407Lys	missense	Exon 6 of 21	ENSP00000558036.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152208 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000170 AC: 42 AN: 247084 AF XY: 0.000171

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000305

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000330 AC: 482 AN: 1460378 Hom.: 0 Cov.: 65 AF XY: 0.000289 AC XY: 210 AN XY: 726404

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86164

European-Finnish (FIN) AF: 0.0000381 AC: 2 AN: 52442

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

European-Non Finnish (NFE) AF: 0.000416 AC: 462 AN: 1111706

Other (OTH) AF: 0.0000994 AC: 6 AN: 60352

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152326 Hom.: 0 Cov.: 34 AF XY: 0.000161 AC XY: 12 AN XY: 74480

African (AFR) AF: 0.0000722 AC: 3 AN: 41580

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000288 Hom.: 0

Bravo AF: 0.000196

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000828 AC: 10

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	Baller-Gerold syndrome (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (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	0.074
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.64
DEOGEN2	Benign	0.013	T
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.094	T
PhyloP100		3.0
PrimateAI	Benign	0.32	T
Sift4G	Uncertain	0.015	D
Polyphen		0.43	B
Vest4		0.32
MVP		0.76
GERP RS		5.5
PromoterAI		0.0046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.39
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs117670586; hg19: chr8-145741187; COSMIC: COSV52882769; COSMIC: COSV52882769;