chr3-37016947-C-T

Variant names:

• chr3-37016947-C-T
• rs4647275
• NM_000249.4:c.791-559C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000249.4(MLH1):​c.791-559C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,317,614 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.016 (38 hom., cov: 33)
  • Exomes 𝑓: 0.021 (323 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.35
• Publications: 1 publications found

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

RPL29P11 (HGNC:36905): (ribosomal protein L29 pseudogene 11)

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 3-37016947-C-T is Benign according to our data. Variant chr3-37016947-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 223828.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0161 (2458/152282) while in subpopulation NFE AF = 0.025 (1699/68034). AF 95% confidence interval is 0.024. There are 38 homozygotes in GnomAd4. There are 1248 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000249.4. 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
	MLH1	NM_000249.4	MANE Select	c.791-559C>T		intron	N/A	NP_000240.1	P40692-1
	MLH1	NM_001354628.2		c.791-559C>T		intron	N/A	NP_001341557.1	A0A087WX20
	MLH1	NM_001354629.2		c.692-559C>T		intron	N/A	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.791-559C>T		intron	N/A	ENSP00000231790.3	P40692-1
	MLH1	ENST00000456676.7	TSL:1	c.791-559C>T		intron	N/A	ENSP00000416687.3	H0Y818
	MLH1	ENST00000413740.2	TSL:1	c.791-559C>T		intron	N/A	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2457 AN: 152164 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00536

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.0207 AC: 24158 AN: 1165332 Hom.: 323 Cov.: 16 AF XY: 0.0202 AC XY: 11959 AN XY: 593134

African (AFR) AF: 0.00384 AC: 107 AN: 27862

American (AMR) AF: 0.00910 AC: 397 AN: 43636

Ashkenazi Jewish (ASJ) AF: 0.00798 AC: 190 AN: 23816

East Asian (EAS) AF: 0.0000778 AC: 3 AN: 38536

South Asian (SAS) AF: 0.00393 AC: 311 AN: 79072

European-Finnish (FIN) AF: 0.0289 AC: 1109 AN: 38332

Middle Eastern (MID) AF: 0.00137 AC: 5 AN: 3642

European-Non Finnish (NFE) AF: 0.0245 AC: 21097 AN: 859656

Other (OTH) AF: 0.0185 AC: 939 AN: 50780

GnomAD4 genome AF: 0.0161 AC: 2458 AN: 152282 Hom.: 38 Cov.: 33 AF XY: 0.0168 AC XY: 1248 AN XY: 74464

African (AFR) AF: 0.00539 AC: 224 AN: 41560

American (AMR) AF: 0.0103 AC: 157 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00476 AC: 23 AN: 4830

European-Finnish (FIN) AF: 0.0297 AC: 315 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0250 AC: 1699 AN: 68034

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.0188 Hom.: 5

Bravo AF: 0.0139

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.4
DANN	Benign	0.97
PhyloP100		3.3
Mutation Taster		=100/0	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: rs4647275; hg19: chr3-37058438;