chr12-6943869-G-GT

Variant names:

• chr12-6943869-G-GT
• rs1174136528
• ENST00000544681.1:c.-253_-252insT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001301834.1(C12orf57):​c.-16+207_-16+208insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000352 in 953,470 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (5 hom.)
• Consequence: C12orf57 NM_001301834.1 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52
• Publications: 0 publications found

Genes affected

C12orf57 (HGNC:29521): (chromosome 12 open reading frame 57) This gene is ubiquitously expressed in human tissues. It is required for development of the human corpus callosum. Mutations in this gene are associated with Temtamy syndrome (TEMTYS). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]

RNU7-1 (HGNC:34033): (RNA, U7 small nuclear 1) Implicated in Aicardi-Goutieres syndrome. [provided by Alliance of Genome Resources, Apr 2022]

RNU7-1 Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 9

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), PanelApp Australia

ENSG00000272173 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000348 (279/801200) while in subpopulation SAS AF = 0.00209 (110/52698). AF 95% confidence interval is 0.00177. There are 5 homozygotes in GnomAdExome4. There are 177 alleles in the male GnomAdExome4 subpopulation. Median coverage is 10. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301834.1. 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
	C12orf57	NM_001301834.1		c.-16+207_-16+208insT		intron	N/A	NP_001288763.1	Q99622
	C12orf57	NM_001301836.2		c.13+207_13+208insT		intron	N/A	NP_001288765.1
	RNU7-1	NR_023317.1		n.54_55insT		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C12orf57	ENST00000544681.1	TSL:2	c.-253_-252insT		5_prime_UTR	Exon 1 of 2	ENSP00000475422.1	U3KQ07
	C12orf57	ENST00000537087.5	TSL:2	c.-253_-252insT		5_prime_UTR	Exon 1 of 3	ENSP00000440937.1	F5GXW5
	C12orf57	ENST00000921170.1		c.-253_-252insT		5_prime_UTR	Exon 1 of 2	ENSP00000591229.1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000348 AC: 279 AN: 801200 Hom.: 5 Cov.: 10 AF XY: 0.000441 AC XY: 177 AN XY: 401512

African (AFR) AF: 0.000446 AC: 8 AN: 17956

American (AMR) AF: 0.000116 AC: 2 AN: 17206

Ashkenazi Jewish (ASJ) AF: 0.000203 AC: 3 AN: 14748

East Asian (EAS) AF: 0.000316 AC: 9 AN: 28466

South Asian (SAS) AF: 0.00209 AC: 110 AN: 52698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23408

Middle Eastern (MID) AF: 0.000382 AC: 1 AN: 2620

European-Non Finnish (NFE) AF: 0.000202 AC: 123 AN: 607942

Other (OTH) AF: 0.000636 AC: 23 AN: 36156

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74450

African (AFR) AF: 0.000481 AC: 20 AN: 41578

American (AMR) AF: 0.000327 AC: 5 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4818

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68000

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000540 Hom.: 0

Bravo AF: 0.000317

Asia WGS AF: 0.00144 AC: 5 AN: 3478

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		2.5
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1174136528; hg19: chr12-7053032;