chr8-144517482-T-G

Variant names:

• chr8-144517482-T-G
• rs1046890336
• NM_004260.4:c.145A>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_004260.4(RECQL4):​c.145A>C​(p.Lys49Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000563 in 1,597,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. 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. K49N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.772
• Publications: 0 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33621413).

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.145A>C	p.Lys49Gln	missense	Exon 3 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.145A>C	p.Lys49Gln	missense	Exon 3 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.145A>C	p.Lys49Gln	missense	Exon 3 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.145A>C	p.Lys49Gln	missense	Exon 3 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.-927A>C		5_prime_UTR	Exon 2 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.145A>C	p.Lys49Gln	missense	Exon 3 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152136 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000140 AC: 3 AN: 214586 AF XY: 0.00000839

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000366

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1445354 Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 2 AN XY: 718400

African (AFR) AF: 0.00 AC: 0 AN: 33280

American (AMR) AF: 0.0000457 AC: 2 AN: 43796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39378

South Asian (SAS) AF: 0.00 AC: 0 AN: 84768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5062

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108482

Other (OTH) AF: 0.0000334 AC: 2 AN: 59910

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152136 Hom.: 0 Cov.: 35 AF XY: 0.0000404 AC XY: 3 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.000262 AC: 4 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000117

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Baller-Gerold syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Benign	0.62
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.34	T
PhyloP100		0.77
PrimateAI	Pathogenic	0.82	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.25
MVP		0.74
GERP RS		4.4
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.38
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1046890336; hg19: chr8-145742866;