NM_016578.4:c.3701A>C

Variant names:

• chr11-77672092-T-G
• rs148454072
• NM_016578.4:c.3701A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_016578.4(RSF1):​c.3701A>C​(p.Lys1234Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0015 in 1,614,122 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: RSF1 NM_016578.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67
• Publications: 5 publications found

Genes affected

RSF1 (HGNC:18118): (remodeling and spacing factor 1) This gene encodes a nuclear protein that interacts with hepatitis B virus X protein (HBX) and facilitates transcription of hepatitis B virus genes by the HBX transcription activator, suggesting a role for this interaction in the virus life cycle. This protein also interacts with SNF2H protein to form the RSF chromatin-remodeling complex, where the SNF2H subunit functions as the nucleosome-dependent ATPase, and this protein as the histone chaperone. [provided by RefSeq, Sep 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07736528).
• BS2: High AC in GnomAd4 at 144 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSF1	NM_016578.4	c.3701A>C	p.Lys1234Thr	missense_variant	Exon 15 of 16	ENST00000308488.11	NP_057662.3
RSF1	XM_005274051.3	c.3692A>C	p.Lys1231Thr	missense_variant	Exon 15 of 16		XP_005274108.1
RSF1	XM_017017923.2	c.3578A>C	p.Lys1193Thr	missense_variant	Exon 15 of 16		XP_016873412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSF1	ENST00000308488.11	c.3701A>C	p.Lys1234Thr	missense_variant	Exon 15 of 16	1	NM_016578.4	ENSP00000311513.6
RSF1	ENST00000480887.5	c.2945A>C	p.Lys982Thr	missense_variant	Exon 10 of 11	1		ENSP00000434509.1

Frequencies

GnomAD3 genomes AF: 0.000946 AC: 144 AN: 152232 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00101 AC: 254 AN: 251272 AF XY: 0.00115

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00156 AC: 2276 AN: 1461772 Hom.: 4 Cov.: 31 AF XY: 0.00153 AC XY: 1112 AN XY: 727190

African (AFR) AF: 0.000418 AC: 14 AN: 33468

American (AMR) AF: 0.000805 AC: 36 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.000812 AC: 70 AN: 86204

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00179 AC: 1985 AN: 1111984

Other (OTH) AF: 0.00263 AC: 159 AN: 60388

GnomAD4 genome AF: 0.000945 AC: 144 AN: 152350 Hom.: 0 Cov.: 31 AF XY: 0.000872 AC XY: 65 AN XY: 74504

African (AFR) AF: 0.000481 AC: 20 AN: 41586

American (AMR) AF: 0.00137 AC: 21 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00141 AC: 96 AN: 68026

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

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.000937

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00114 AC: 139

EpiCase AF: 0.00142

EpiControl AF: 0.00148

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3701A>C (p.K1234T) alteration is located in exon 15 (coding exon 15) of the RSF1 gene. This alteration results from a A to C substitution at nucleotide position 3701, causing the lysine (K) at amino acid position 1234 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.077	T;T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.0	M;.
PhyloP100		3.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.4	N;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;.
Vest4		0.52
MVP		0.51
MPC		0.77
ClinPred		0.053	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.12
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs148454072; hg19: chr11-77383137; COSMIC: COSV99074536; COSMIC: COSV99074536;