NM_004260.4:c.3435G>C

Variant names:

• chr8-144511748-C-G
• rs61755066
• NM_004260.4:c.3435G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004260.4(RECQL4):​c.3435G>C​(p.Gln1145His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,612,612 control chromosomes in the GnomAD database, including 14 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1145K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0034 (12 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.367
• Publications: 5 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043895543).
• BP6: Variant 8-144511748-C-G is Benign according to our data. Variant chr8-144511748-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.3435G>C	p.Gln1145His	missense	Exon 20 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.3510G>C	p.Gln1170His	missense	Exon 19 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.3444G>C	p.Gln1148His	missense	Exon 20 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.3435G>C	p.Gln1145His	missense	Exon 20 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.2364G>C	p.Gln788His	missense	Exon 19 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.3342G>C	p.Gln1114His	missense	Exon 20 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 385 AN: 152264 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000915

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00696

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00388

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00296 AC: 732 AN: 247644 AF XY: 0.00296

Gnomad AFR exome AF: 0.000718

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000400

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00693

Gnomad NFE exome AF: 0.00457

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00338 AC: 4935 AN: 1460230 Hom.: 12 Cov.: 36 AF XY: 0.00326 AC XY: 2370 AN XY: 726392

African (AFR) AF: 0.000478 AC: 16 AN: 33478

American (AMR) AF: 0.00121 AC: 54 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 17 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00796 AC: 414 AN: 52036

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00382 AC: 4248 AN: 1111792

Other (OTH) AF: 0.00305 AC: 184 AN: 60346

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152382 Hom.: 2 Cov.: 34 AF XY: 0.00266 AC XY: 198 AN XY: 74522

African (AFR) AF: 0.000697 AC: 29 AN: 41594

American (AMR) AF: 0.000914 AC: 14 AN: 15314

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00696 AC: 74 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00388 AC: 264 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00294 Hom.: 1

Bravo AF: 0.00226

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000460 AC: 2

ESP6500EA AF: 0.00375 AC: 32

ExAC AF: 0.00333 AC: 403

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (4)
-	-	1	Baller-Gerold syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.63
DANN	Benign	0.74
DEOGEN2	Benign	0.0057	T
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0044	T
MutationAssessor	Benign	0.64	N
PhyloP100		-0.37
PrimateAI	Benign	0.32	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.31
MVP		0.64
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.23
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61755066; hg19: chr8-145737131; COSMIC: COSV104618547;