NM_004260.4:c.3622C>T

Variant names:

• chr8-144511436-G-A
• rs41555416
• NM_004260.4:c.3622C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004260.4(RECQL4):​c.3622C>T​(p.Arg1208Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000884 in 1,612,340 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 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. R1208G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00089 (1 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 1.77
• 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]

SLC33A2 (HGNC:25157): (major facilitator superfamily domain containing 3) Predicted to enable solute:proton symporter activity. Predicted to be involved in proton transmembrane transport. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012305528).

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.3622C>T	p.Arg1208Cys	missense	Exon 21 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.3697C>T	p.Arg1233Cys	missense	Exon 20 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.3631C>T	p.Arg1211Cys	missense	Exon 21 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.3622C>T	p.Arg1208Cys	missense	Exon 21 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.2551C>T	p.Arg851Cys	missense	Exon 20 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.3529C>T	p.Arg1177Cys	missense	Exon 21 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.000801 AC: 122 AN: 152220 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000581 AC: 144 AN: 247918 AF XY: 0.000526

Gnomad AFR exome AF: 0.000261

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000893 AC: 1304 AN: 1460002 Hom.: 1 Cov.: 33 AF XY: 0.000863 AC XY: 627 AN XY: 726220

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.000336 AC: 15 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.000250 AC: 13 AN: 52066

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00111 AC: 1237 AN: 1111576

Other (OTH) AF: 0.000530 AC: 32 AN: 60338

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152338 Hom.: 0 Cov.: 34 AF XY: 0.000671 AC XY: 50 AN XY: 74496

African (AFR) AF: 0.000385 AC: 16 AN: 41578

American (AMR) AF: 0.000980 AC: 15 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68020

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000792 Hom.: 0

Bravo AF: 0.000725

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000710 AC: 3

ESP6500EA AF: 0.000355 AC: 3

ExAC AF: 0.000554 AC: 67

EpiCase AF: 0.000981

EpiControl AF: 0.000830

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	-	RECQL4-related disorder (1)
-	1	-	Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Benign	0.66
DEOGEN2	Benign	0.037	T
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.012	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.8
PrimateAI	Benign	0.23	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0020	B
Vest4		0.17
MVP		0.40
GERP RS		0.35
Varity_R		0.088
gMVP		0.57
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs41555416; hg19: chr8-145736819; COSMIC: COSV56741386; COSMIC: COSV56741386;