rs4994616

Variant names:

• chr1-151574912-A-C
• rs4994616
• NM_020127.3:c.725A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020127.3(TUFT1):​c.725A>C​(p.Glu242Ala) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUFT1 NM_020127.3 missense, splice_region
• Scores: Splicing: ADA: 0.8253
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.41
• Publications: 1 publications found

Genes affected

TUFT1 (HGNC:12422): (tuftelin 1) Tuftelin is an acidic protein that is thought to play a role in dental enamel mineralization and is implicated in caries susceptibility. It is also thought to be involved with adaptation to hypoxia, mesenchymal stem cell function, and neurotrophin nerve growth factor mediated neuronal differentiation. [provided by RefSeq, Aug 2014]

TUFT1 Gene-Disease associations (from GenCC):

• woolly hair-skin fragility syndrome

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020127.3. 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
	TUFT1	NM_020127.3	MANE Select	c.725A>C	p.Glu242Ala	missense splice_region	Exon 9 of 13	NP_064512.1	Q9NNX1-1
	TUFT1	NM_001301317.2		c.782A>C	p.Glu261Ala	missense splice_region	Exon 10 of 14	NP_001288246.1
	TUFT1	NM_001126337.2		c.650A>C	p.Glu217Ala	missense splice_region	Exon 8 of 12	NP_001119809.1	Q9NNX1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUFT1	ENST00000368849.8	TSL:1 MANE Select	c.725A>C	p.Glu242Ala	missense splice_region	Exon 9 of 13	ENSP00000357842.3	Q9NNX1-1
	TUFT1	ENST00000368848.6	TSL:1	c.650A>C	p.Glu217Ala	missense splice_region	Exon 8 of 12	ENSP00000357841.2	Q9NNX1-2
	TUFT1	ENST00000873676.1		c.725A>C	p.Glu242Ala	missense splice_region	Exon 9 of 13	ENSP00000543735.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.78
MVP		0.81
MPC		0.60
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.64
gMVP		0.63
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Pathogenic	0.79
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: rs4994616; hg19: chr1-151547388;