NM_001330360.2:c.95_96insTGA

Variant names:

• chrX-24699475-A-AATG
• NM_001330360.2:c.95_96insTGA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_001330360.2(POLA1):​c.95_96insTGA​(p.Lys32delinsAsnGlu) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K32K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: POLA1 NM_001330360.2 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83
• Publications: 0 publications found

Genes affected

POLA1 (HGNC:9173): (DNA polymerase alpha 1, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase, which together with a regulatory and two primase subunits, forms the DNA polymerase alpha complex. The catalytic subunit plays an essential role in the initiation of DNA replication. [provided by RefSeq, Mar 2010]

POLA1 Gene-Disease associations (from GenCC):

• X-linked intellectual disability, van Esch type

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• X-linked reticulate pigmentary disorder

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001330360.2. Strenght limited to Supporting due to length of the change: 1aa.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330360.2. 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
	POLA1	NM_001330360.2	MANE Select	c.95_96insTGA	p.Lys32delinsAsnGlu	disruptive_inframe_insertion	Exon 2 of 37	NP_001317289.1	A6NMQ1
	POLA1	NM_001440806.1		c.95_96insTGA	p.Lys32delinsAsnGlu	disruptive_inframe_insertion	Exon 2 of 38	NP_001427735.1
	POLA1	NM_016937.4		c.77_78insTGA	p.Lys26delinsAsnGlu	disruptive_inframe_insertion	Exon 2 of 37	NP_058633.2	P09884

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLA1	ENST00000379068.8	TSL:5 MANE Select	c.95_96insTGA	p.Lys32delinsAsnGlu	disruptive_inframe_insertion	Exon 2 of 37	ENSP00000368358.3	A6NMQ1
	POLA1	ENST00000379059.7	TSL:1	c.77_78insTGA	p.Lys26delinsAsnGlu	disruptive_inframe_insertion	Exon 2 of 37	ENSP00000368349.3	P09884
	POLA1	ENST00000933044.1		c.77_78insTGA	p.Lys26delinsAsnGlu	disruptive_inframe_insertion	Exon 2 of 38	ENSP00000603103.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chrX-24717592;