1-23787339-T-C

Variant names:

• chr1-23787339-T-C
• rs1024316788
• NM_020362.5:c.599T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020362.5(PITHD1):​c.599T>C​(p.Val200Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V200D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PITHD1 NM_020362.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.87
• Publications: 0 publications found

Genes affected

PITHD1 (HGNC:25022): (PITH domain containing 1) Involved in positive regulation of megakaryocyte differentiation and positive regulation of transcription, DNA-templated. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13034299).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020362.5. 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
	PITHD1	NM_020362.5	MANE Select	c.599T>C	p.Val200Ala	missense	Exon 6 of 6	NP_065095.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITHD1	ENST00000246151.9	TSL:1 MANE Select	c.599T>C	p.Val200Ala	missense	Exon 6 of 6	ENSP00000246151.4	Q9GZP4-1
	PITHD1	ENST00000873427.1		c.587T>C	p.Val196Ala	missense	Exon 6 of 6	ENSP00000543486.1
	PITHD1	ENST00000374524.1	TSL:3	c.260T>C	p.Val87Ala	missense	Exon 4 of 4	ENSP00000363648.1	X6R8S9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459936 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 726400

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110348

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.079
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.55	N
PhyloP100		7.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.15
Sift	Benign	0.41	T
Sift4G	Benign	0.89	T
Polyphen		0.0020	B
Vest4		0.22
MutPred		0.26		Loss of stability (P = 0.01)
MVP		0.41
MPC		0.42
ClinPred		0.50	T
GERP RS		5.8
Varity_R		0.048
gMVP		0.61
Mutation Taster		=53/47	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: rs1024316788; hg19: chr1-24113829;