8-144517733-A-G

Variant names:

• chr8-144517733-A-G
• rs941281893
• NM_004260.4:c.52T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004260.4(RECQL4):​c.52T>C​(p.Phe18Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,349,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. F18S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.188
• 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]

LRRC14 (HGNC:20419): (leucine rich repeat containing 14) This gene encodes a leucine-rich repeat-containing protein. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40845495).

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.52T>C	p.Phe18Leu	missense	Exon 1 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.52T>C	p.Phe18Leu	missense	Exon 1 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.52T>C	p.Phe18Leu	missense	Exon 1 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.52T>C	p.Phe18Leu	missense	Exon 1 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.-1085T>C		5_prime_UTR	Exon 1 of 20	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.52T>C	p.Phe18Leu	missense	Exon 1 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150718 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000444

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000245 AC: 1 AN: 40892 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000671

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000292 AC: 35 AN: 1198966 Hom.: 0 Cov.: 32 AF XY: 0.0000273 AC XY: 16 AN XY: 586292

African (AFR) AF: 0.0000420 AC: 1 AN: 23826

American (AMR) AF: 0.00 AC: 0 AN: 16424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18396

East Asian (EAS) AF: 0.00 AC: 0 AN: 25660

South Asian (SAS) AF: 0.00 AC: 0 AN: 52684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28026

Middle Eastern (MID) AF: 0.000299 AC: 1 AN: 3348

European-Non Finnish (NFE) AF: 0.0000326 AC: 32 AN: 982346

Other (OTH) AF: 0.0000207 AC: 1 AN: 48256

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150718 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 73564

African (AFR) AF: 0.00 AC: 0 AN: 41164

American (AMR) AF: 0.00 AC: 0 AN: 15150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67540

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Baller-Gerold syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Benign	0.42
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.41	T
PhyloP100		0.19
PrimateAI	Pathogenic	0.92	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.31
MVP		0.52
GERP RS		3.4
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Varity_R		0.82
gMVP		0.34
Mutation Taster		=91/9	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: rs941281893; hg19: chr8-145743117;